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Mechanotransduction and Vascular Resistance

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PanVascular Medicine

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Abstract

Mechanotransduction is the process by which any cell transduces (converts) a mechanical signal into chemical cues. The vessel wall is permanently sheared by the moving blood particles as well as stretched and compressed by the pressure applied by the blood. Multiple types of mechanical stress fields are associated with flow patterns and unsteadiness.

Mechanosensing occurs locally at the plasma membrane. It relies on detection of local changes in protein conformation that lead to ion channel opening, protein unfolding, modified enzyme kinetics, and variations in molecular interactions following exposure of buried binding site or, conversely, hiding them.

Mechanotransduction initiates several signaling pathways. Multiple mediators include:

  1. 1.

    At the cell surface, G-protein-coupled and protein tyrosine kinase receptors, ion channels, enzymes, adhesion molecules, and specialized plasmalemmal nanodomains

  2. 2.

    At the cell cortex, the cortical actin network that regulates the cell-surface mechanics and signaling adaptors and effectors (e.g., small monomeric guanosine triphosphatases and heterotrimeric guanine nucleotide-binding proteins, kinases, phosphatases, and ubiquitins, among others)

  3. 3.

    In the cytosol, enzymes, scaffolds, carriers such as endosomes, calcium concentration, and transcription factors

  4. 4.

    In the nucleus, nuclear pore carriers, enzymes, and the transcriptional and translational machinery

Mechanotransduction by vascular cells regulate the contraction–relaxation state of vascular smooth myocytes, thereby regulating locally and quickly the size of the vascular lumen, that is, the local vascular resistance to blood flow. Once experiencing an unusual mechanical stress, vascular smooth myocytes react by contracting or relaxing according to the magnitude of the mechanical stress, the value of which rises above or falls below the range in which it fluctuates in normal conditions. Moreover, they receive chemical and electrochemical signals from endotheliocytes, themselves sensing the wall shear stress at their wetted (luminal) surface.

Mechanotransduction thus regulates locally blood flow more rapidly than the endocrine regulation by remote tissues and even than that of the nervous system, which transmits signals very rapidly via afferent nerves and, after processing in the centers of the spinal cord and brain, efferent nerves.

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Abbreviations

Adherens junctions:

Also named zonula adherens and belt desmosome, are proteic complexes that ensure intercellular junctions in endo- and epithelia, usually situated more basally than tight junctions. In cardiomyocytes, fascia adherens are structurally similar, but do not completely encircle the cell. Adherens junctions are linked to the actin cytoskeleton. Adherens junctions are composed of:

  • Transmembrane cadherins that homodimerize in a calcium-dependent manner with cadherins on apposed cells

  • δ-Catenin that binds to the juxtamembrane region of cadherins

  • γ-Catenin (or plakoglobin) that tethers to the catenin-binding region of cadherins

  • α-Catenin that connects to cadherin via β- or γ-catenin and the actin cytoskeleton

Cytoskeleton intracellular meshwork:

Made of three main categories of filaments, microfilaments, microtubules, and intermediate filaments.

Microfilaments, or actomyosin filaments, are involved in cell adaptation to the local mechanical stress field. They form contractile stress fibers. They are involved in cell shape, contraction, and displacement, as well as intracellular transport.

Microtubules are polymers of α- and β-tubulin. They form centrioles and cilia. They operate in intracellular transport with dyneins and kinesins and form the mitotic spindle. Microtubules resist compression.

Intermediate filaments consist commonly of vimentins but also of keratin in skin cells and neurofilaments in neural cells. In the nucleus, the nucleoskeleton being connected to the cytoskeleton, they are built from lamin. They contribute to the maintenance of the cellular shape, as they can bear tension.

Eicosanoids:

Set of molecules that include leukotrienes, lipoxins, prostacyclins, prostaglandins, and thromboxanes.

Endothelium-dependent hyperpolarization factor (EDHF):

Set of chemicals that comprise K+ ion, nitric oxide, prostaglandins, cytochrome P450 products epoxyeicosatrienoic acids (EET), and myoendothelial electrical coupling, implicated in vasodilation.

Gap junction or nexus:

An intercellular adhesion between adjoining cells that connects the cytoplasm of these cells, thereby enabling transfer of various small molecules and ions, among which small second messengers, thereby ensuring electrical and metabolic coupling.

It is composed of two connexons (hemichannels) that link in the intercellular space. These homo- and heterohexamers of transmembrane connexins form homomeric and heteromeric hemichannels, respectively. Two identical connexons build a homotypic gap junction, whereas a homomeric and a heteromeric connexon as well as two heteromeric connexons create a heterotypic gap junction.

Gasotransmitters:

Set of endogenous, gaseous, diffusible signaling mediators that includes nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S).

Glycocalyx extracellular polymeric matrix:

Made of glycoproteins, proteoglycans, and glycolipids. It is attached to the external surface of the plasma membrane. It contributes to between cell recognition and communication.

The endothelial glycocalyx covers the luminal wetted surface. It participates in mechanotransduction, hemostasis, signaling, interactions between endothelium and flowing leukocytes and platelets, and mass transfer from the blood to the vascular wall. It contributes to the 1.2-μm-thick plasma layer in the microcirculation. Glycosaminoglycans of the glycocalyx, such as heparan sulfate glycosaminoglycans and hyaluronan, operate as mechanotransducers.

G-protein-coupled receptors or 7-transmembrane domain receptors:

Associated with guanosine nucleotide-binding proteins (G proteins). Once they are activated, they undergo a conformational change that allows them to act as a guanine nucleotide-exchange factor activating G protein by exchanging its bound GDP for a GTP. These receptors sense molecules outside the cell and initiate signaling pathways. They also convert mechanical strains and stresses into chemical and electrical signals (mechanosensation, or mechanoreception, and mechanotransduction).

Integrins:

Major receptors that connect the cytoskeleton to the extracellular matrix sense and transmit across the plasma membrane mechanical stresses emitted by the cell or its environment. Integrins contribute to the control of signaling pathways.

Upon integrin binding to matrix ligands, integrins attach to the actin cytoskeleton and increase cellular adhesion strength. Early adhesions mature to focal complexes by recruiting paxillin and vinculin. Vinculin concentration in adhesion sites is correlated linearly with traction. Focal complexes are precursors to focal adhesions that are created via activation of small Rho GTPases. The latter increases cellular contractility via RoCK kinase that phosphorylates myosin light-chain kinase as well as assembly of fibrillar adhesions and fibronectin meshwork. Stretch also remodels focal adhesions. Receptor (plasmalemmal) and cytosolic protein tyrosine phosphatases are implicated in force-dependent adhesion reinforcement upon stretch.

Shear stress exerted by the blood on endotheliocytes regulates vascular tone and wall remodeling via α5β1- and αVβ3-integrins.

Isoprostanes:

Unconventional eicosanoids formed from nonenzymatic peroxidation of membrane fatty acids such as arachidonic acid by free radicals and other types of reactive oxygen species, without direct action of cyclooxygenases.

Mechanosensitive ion channels:

Plasmalemmal proteins that include various categories from nonselective to highly selective ion channels sensitive to mechanical stress. They generate electrochemical signals.

Myoendothelial junction:

Junction between an endothelial projection that protrudes and crosses holes of the endothelial basement membrane and internal elastic lamina and adjacent smooth myocyte. It is involved in the regulation of the vasomotor tone.

Myogenic response:

Response caused by a change in arterial pressure, in particular in the cerebral, coronary, and renal arteries, independently of the action of the vascular endothelium. It is associated with blood flow autoregulation, an ability of small resistance arteries and arterioles to reduce or increase their calibers in response to changes in intravascular pressure.

Reactive nitrogen species (RNS):

Radical nitrogen-based molecules facilitating nitrosylation reactions. Nonneutralized RNSs induce nitrative stresses.

Reactive oxygen species (ROS):

Natural by-product involved in cell signaling. However, when they accumulate, they cause an oxidative stress. They include radicals (superoxide) and nonradical reactive oxygen derivatives. Preventive antioxidant proteins (albumin, transferrin, myoglobin, ferritin, etc.) hamper ROS formation. Scavenger lipid- and water-soluble antioxidants (vitamins C and E, α- and β-carotene, superoxide dismutase, hydrogen peroxide, and glutathione peroxidase) remove reactive oxygen species.

Tight junction:

Also termed occluding junctions or zonula occludens, forms a strong barrier with tiny gaps in the cleft between adjacent cells, plasma membranes of which are joined together by sealing strands. Tight junctions are composed of:

  • Transmembrane claudins

  • Integral membrane occludin

  • Cortical zonula occludens proteins ZO1 and ZO2 that anchor the strands to the actin cytoskeleton

References

  • Aaronson PI (2012) Does TRPC3 macrodominate the myoendothelial gap junction microdomain? Cardiovasc Res 95:399–400

    Article  CAS  PubMed  Google Scholar 

  • Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60:79–127

    Article  CAS  PubMed  Google Scholar 

  • Alexander SPH, Mathie A, Peters JA (2007) Guide to receptors and channels. Br J Pharmacol 150:S1–S168, www3.interscience.wiley.com/journal/122684220/issue

  • Allen BW, Stamler JS, Piantadosi CA (2009) Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation. Trends Mol Med 15:452–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alzawahra WF, Talukder MAH, Liu X, Samouilov A, Zweier JL (2008) Heme proteins mediate the conversion of nitrite to nitric oxide in the vascular wall. Am J Physiol Heart Circ Physiol 295:H499–H508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andersson M, Karlsson L, Svensson PA, Ulfhammer E, Ekman M, Jernas M, Carlsson LM, Jern S (2005) Differential global gene expression response patterns of human endothelium exposed to shear stress and intraluminal pressure. J Vasc Res 42:441–452

    Article  CAS  PubMed  Google Scholar 

  • Bao X, Lu C, Frangos JA (2001) Mechanism of temporal gradients in shear-induced ERK1/2 activation and proliferation in endothelial cells. Am J Physiol Heart Circ Physiol 281:22–29

    Google Scholar 

  • Barakat AI, Leaver EV, Pappone PA, Davies PF (1999) A flow-activated chloride-selective membrane current in vascular endothelial cells. Circ Res 85:820–828

    Article  CAS  PubMed  Google Scholar 

  • Barbee KA, Davies PF, Ratneshwar L (1994) Shear stress-induced reorganization of the surface topography of living endothelial cells imaged by atomic force microscopy. Circ Res 74:163–171

    Article  CAS  PubMed  Google Scholar 

  • Barbee KA, Mundel T, Lal R, Davies PF (1995) Subcellular distribution of shear stress at the surface of flow-aligned and nonaligned endothelial monolayers. Am J Physiol Heart Circ Physiol 268:1765–1772

    Google Scholar 

  • Bauersachs J, Popp R, Hecker M, Sauer E, Fleming I, Busse R (1996) Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation 94:3341–3347

    Article  CAS  PubMed  Google Scholar 

  • Baumgarten CM (2007) Origin of mechanotransduction: stretch-activated Ion channels, Chapter 2. In: Weckstrom M, Tavi P (eds) Cardiac mechanotransduction. Landes Bioscience/Springer, Austin/New York

    Google Scholar 

  • Bearden SE, Beard RS Jr, Pfau JC (2010) Extracellular transsulfuration generates hydrogen sulfide from homocysteine and protects endothelium from redox stress. Am J Physiol Heart Circ Physiol 299:H1568–H1576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beaucourt J, Biben T, Misbah C (2004) Optimal lift force on vesicles near a compressible substrate. Europhys Lett 67:676–682

    Article  CAS  Google Scholar 

  • Beaudin AE, Brugniaux JV, Vöhringer M, Flewitt J, Green JD, Friedrich MG, Poulin MJ (2011) Cerebral and myocardial blood flow responses to hypercapnia and hypoxia in humans. Am J Physiol Heart Circ Physiol 301:H1678–H1686

    Article  CAS  PubMed  Google Scholar 

  • Benavides GA, Squadrito GL, Mills RW, Patel HD, Isbell TS, Patel RP, Darley-Usmar VM, Doeller JE, Kraus DW (2007) Hydrogen sulfide mediates the vasoactivity of garlic. Proc Natl Acad Sci USA 104:17977–17982

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bergfeld GR, Forrester T (1992) Release of ATP from human erythrocytes in response to a brief period of hypoxia and hypercapnia. Cardiovasc Res 26:40–47

    Article  CAS  PubMed  Google Scholar 

  • Bhullar IS, Li YS, Miao H, Zandi E, Kim M, Shyy JY, Chien S (1998) Fluid shear stress activation of IkappaB kinase is integrin-dependent. J Biol Chem 273:30544–30549

    Article  CAS  PubMed  Google Scholar 

  • Böhm F, Pernow J (2007) The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res 76:8–18

    Article  PubMed  CAS  Google Scholar 

  • Boittin FX, Gribi F, Serir K, Bény JL (2008) Ca2+ -Independent PLA2 controls endothelial store-operated Ca2+ entry and vascular tone in intact aorta. Am J Physiol Heart Circ Physiol 295:H2466–H2474

    Article  CAS  PubMed  Google Scholar 

  • Bonini MG, Stadler K, de Oliveira SS, Corbett J, Dore M, Petranka J, Fernandes DC, Tanaka LY, Duma D, Laurindo FRM, Mason RP (2008) Constitutive nitric oxide synthase activation is a significant route for nitroglycerin-mediated vasodilation. Proc Natl Acad Sci USA 105:8569–8574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burnstock G (2006) Vessel tone and remodeling. Nat Med 12:16–17

    Article  CAS  PubMed  Google Scholar 

  • Burridge K, Fath K, Kelly T, Nuckolls G, Turner C (1988) Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol 4:1487–1525

    Article  Google Scholar 

  • Cai H (2006) Potassium channel as endothelial mechanosensor and modulator of NAD(P)H oxidase: new mechanism for flow-mediated vasoprotection. Am J Physiol Cell Physiol 290:C35–C36

    Article  CAS  PubMed  Google Scholar 

  • Cai WJ, Wang MJ, Moore PK, Jin HM, Yao T, Zhu YC (2007) The novel proangiogenic effect of hydrogen sulfide is dependent on Akt phosphorylation. Cardiovasc Res 76:29–40

    Article  CAS  PubMed  Google Scholar 

  • Cao Z, Bell JB, Mohanty JG, Nagababu E, Rifkind JM (2009) Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation. Am J Physiol Heart Circ Physiol 297:H1494–H1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Capettini LS, Cortes SF, Gomes MA, Silva GA, Pesquero JL, Lopes MJ, Teixeira MM, Lemos VS (2008) Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor. Am J Physiol Heart Circ Physiol 295:H2503–H2511

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oostuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, de Ruiter MC, Gittenbergerde Groot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E (1999) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98:147–157

    Article  CAS  PubMed  Google Scholar 

  • Castier Y, Brandes RP, Leseche G, Tedgui A, Lehoux S (2005) p47phox-dependent NADPH oxidase regulates flow-induced vascular remodeling. Circ Res 97:533–540

    Article  CAS  PubMed  Google Scholar 

  • Chadha PS, Liu L, Rikard-Bell M, Senadheera S, Howitt L, Bertrand RL, Grayson TH, Murphy TV, Sandow SL (2011) Endothelium-dependent vasodilation in human mesenteric artery is primarily mediated by myoendothelial gap junctions intermediate conductance calcium-activated K+ channel and nitric oxide. J Pharmacol Exp Ther 336:701–708

    Article  CAS  PubMed  Google Scholar 

  • Chan CK, Vanhoutte PM (2011) Secretoneurin facilitates endothelium-dependent relaxations in porcine coronary arteries. Am J Physiol Heart Circ Physiol 300:H1159–H1165

    Article  CAS  PubMed  Google Scholar 

  • Chawengsub Y, Gauthier KM, Campbell WB (2009) Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone. Am J Physiol Heart Circ Physiol 297:H495–H507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JY (1999) Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc. J Biol Chem 274:18393–18400

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Peng IC, Cui X, Li YS, Chien S, Shyy JY (2010) Shear stress, SIRT1, and vascular homeostasis. Proc Natl Acad Sci USA 107:10268–10273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chicurel ME, Chen CS, Ingber DE (1998) Cellular control lies in the balance of forces. Curr Opin Cell Biol 10:232–239

    Article  CAS  PubMed  Google Scholar 

  • Conway DE, Sakurai Y, Weiss D, Vega JD, Taylor WR, Jo H, Eskin SG, Marcus CB, McIntire LV (2009) Expression of CYP1A1 and CYP1B1 in human endothelial cells: regulation by fluid shear stress. Cardiovasc Res 81:669–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE, Schmidt M, Mathur J, Dubin AE, Montal M, Patapoutian A (2012) Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483:176–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dardik A, Chen L, Frattini J, Asada H, Aziz F, Kudo FA, Sumpio BE (2005a) Differential effects of orbital and laminar shear stress on endothelial cells. J Vasc Surg 41:869–880

    Article  PubMed  Google Scholar 

  • Dardik A, Yamashita A, Aziz F, Asada H, Sumpio BE (2005b) Shear stress-stimulated endothelial cells induce smooth muscle cell chemotaxis via platelet-derived growth factor-BB and interleukin-1alpha. J Vasc Surg 41:321–331

    Article  PubMed  Google Scholar 

  • Davies PF, Tripathi SC (1993) Mechanical stress mechanisms and the cell. An endothelial paradigm. Circ Res 72:239–245

    Article  CAS  PubMed  Google Scholar 

  • Davies PF, Robotewskyj A, Griem ML (1994) Quantitative studies of endothelial cell adhesion. Directional remodeling of focal adhesion sites in response to flow forces. J Clin Invest 93:2031–2038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davies PF, Mundel T, Barbee KA (1995) A mechanism for heterogeneous endothelial responses to flow in vivo and in vitro. J Biomech 28:1553–1560

    Article  CAS  PubMed  Google Scholar 

  • Davis MJ, Donovitz JA, Hood JD (1992a) Stretch-activated single-channel and whole-cell currents in vascular smooth muscle cells. Am J Physiol Cell Physiol 262:1083–1088

    Google Scholar 

  • Davis MJ, Meininger GA, Zawieja DC (1992b) Stretch-induced increases in intracellular calcium in isolated vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 263:1292–1299

    Google Scholar 

  • De Paola N, Dewey CF, Davies PF, Gimbrone MA (1992) Vascular endothelium responds to fluid shear stress gradients. Arterioscler Thromb Vasc Biol 12:1254–1259

    Article  Google Scholar 

  • Dekker RJ, van Soest S, Fontijn RD, Salamanca S, de Groot PG, VanBavel E, Pannekoek H, Horrevoets AJ (2002) Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Kruppel-like factor (KLF2). Blood 100:1689–1698

    Article  CAS  PubMed  Google Scholar 

  • Dekker RJ, van Thienen JV, Rohlena J, de Jager SC, Elderkamp YW, Seppen J, de Vries CJ, Biessen EA, van Berkel TJ, Pannekoek H, Horrevoets AJ (2005) Endothelial KLF2 links local arterial shear stress levels to the expression of vascular tone-regulating genes. Am J Pathol 167:609–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeMaio L, Chang YS, Gardner TW, Tarbell JM, Antonetti DA (2001) Shear stress regulates occludin content and phosphorylation. Am J Physiol Heart Circ Physiol 281:105–113

    Google Scholar 

  • Dettmann ES, Vysniauskiene I, Wu R, Flammer J, Haefliger IO (2003) Adrenomedullin-induced endothelium-dependent relaxation in porcine ciliary arteries. Invest Ophthalmol Vis Sci 44:3961–3966

    Article  PubMed  Google Scholar 

  • Dimmeler S, Hermann C, Galle J, Zeiher AM (1999) Upregulation of superoxide dismutase and nitric oxide synthase mediates the apoptosis-suppressive effects of shear stress on endothelial cells. Arterioscler Thromb Vasc Biol 19:656–664

    Article  CAS  PubMed  Google Scholar 

  • Ebong EE, Macaluso FP, Spray DC, Tarbell JM (2011) Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler Thromb Vasc Biol 31:1908–1915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH (1998) K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396:269–272

    Article  CAS  PubMed  Google Scholar 

  • Ellsworth ML, Forrester T, Ellis CG, Dietrich HH (1995) The erythrocyte as a regulator of vascular tone. Am J Physiol Heart Circ Physiol 269:H2155–H2161

    CAS  Google Scholar 

  • Fadini GP, Avogaro A (2010) Cell-based methods for ex vivo evaluation of human endothelial biology. Cardiovasc Res 87:12–21

    Article  CAS  PubMed  Google Scholar 

  • Faraci FM (2006) Reactive oxygen species: influence on cerebral vascular tone. J Appl Physiol 100:739–743

    Article  CAS  PubMed  Google Scholar 

  • Faraci FM, Breese KR, Heistad DD (1994) Cerebral vasodilation during hypercapnia. Role of glibenclamide-sensitive potassium channels and nitric oxide. Stroke 25:1679–1683

    Article  CAS  PubMed  Google Scholar 

  • Fellner SK, Arendshorst WJ (2010) Complex interactions of NO/cGMP/PKG systems on Ca2+ signaling in afferent arteriolar vascular smooth muscle. Am J Physiol Heart Circ Physiol 298:H144–H151

    Article  CAS  PubMed  Google Scholar 

  • Fleming I (2001) Cytochrome P450 and vascular homeostasis. Circ Res 89:753–762

    Article  CAS  PubMed  Google Scholar 

  • Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM (2003) Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res 93:e136–e142

    Article  CAS  PubMed  Google Scholar 

  • Frangos JA, Eskin SG, McIntire LV, Ives CL (1985) Flow effects on prostacyclin production by cultured human endothelial cells. Science 227:1477–1479

    Article  CAS  PubMed  Google Scholar 

  • Franke RP, Gräfe M, Schnittler H, Seiffge D, Mittermayer D, Drenckhahn D (1984) Induction of human vascular endothelial stress fibers by fluid shear stress. Nature 307:648–649

    Article  CAS  PubMed  Google Scholar 

  • Frazziano G, Champion HC, Pagano PJ (2012) NADPH oxidase-derived ROS and the regulation of pulmonary vessel tone. Am J Physiol Heart Circ Physiol 302:H2166–H2177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujiwara K, Masuda M, Osawa M, Kano Y, Katoh K (2001) Is PECAM-1 a mechanoresponsive molecule? Cell Struct Funct 26:11–17

    Article  CAS  PubMed  Google Scholar 

  • Fung YC, Liu SQ (1993) Elementary mechanics of the endothelium of blood vessels. J Biomech Eng 115:1–12

    Article  CAS  PubMed  Google Scholar 

  • Furchgott RF, Zawadzki JV (1980) The obligatory role of the endothelium in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  CAS  PubMed  Google Scholar 

  • Galley HF, Webster NR (2004) Physiology of the endothelium. Br J Anaesth 93:105–113

    Article  CAS  PubMed  Google Scholar 

  • Ganguli A, Persson L, Palmer IR, Evans I, Yang L, Smallwood R, Black R, Qwarnstrom EE (2005) Distinct NF-κB regulation by shear stress through Ras-dependent IκBα oscillations. Circ Res 96:626–634

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Cardena G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, Lisanti MP, Sessa WC (1997) Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the NOS caveolin binding domain in vivo. J Biol Chem 272:25437–25440

    Article  CAS  PubMed  Google Scholar 

  • Gilchrist M, Shore AC, Benjamin N (2011) Inorganic nitrate and nitrite and control of blood pressure. Cardiovasc Res 89:492–498

    Article  CAS  PubMed  Google Scholar 

  • Gladwin MT, Raat NJ, Shiva S, Dezfulian C, Hogg N, Kim-Shapiro DB, Patel RP (2006) Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 291:H2026–H2035

    Article  CAS  PubMed  Google Scholar 

  • Gokina NI, Kuzina OY, Vance AM (2010) Augmented EDHF signaling in rat uteroplacental vasculature during late pregnancy. Am J Physiol Heart Circ Physiol 299:H1642–H1652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Granata F, Potenza RL, Fiori A, Strom R, Caronti B, Molinari P, Donsante S, Citro G, Iacovelli L, De Blasi A, Ngomba RT, Palladini G, Passarelli F (2003) Expression of OP4 (ORL1, NOP1) receptors in vascular endothelium. Eur J Pharmacol 482:17–23

    Article  CAS  PubMed  Google Scholar 

  • Gudi SRP, Huver IV, Taliana AP, Boss GR, Frangos JA (1997) Fluid flow-induced ras activation is mediated by Gaq in human vascular endothelial cells. FASEB J 11:A223

    Google Scholar 

  • Gudi S, Nolan JP, Frangos JA (1998) Modulation of GTPase activity of G proteins by fluid shear stress and phospholipid composition. Proc Natl Acad Sci USA 95:2515–2519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gui Y, Walsh MP, Jankowski V, Jankowski J, Zheng XL (2008) Up4A stimulates endothelium-independent contraction of isolated rat pulmonary artery. Am J Physiol Lung Cell Mol Physiol 294:L733–L738

    Article  CAS  PubMed  Google Scholar 

  • Hao H, Ropraz P, Verin V, Camenzind E, Geinoz A, Pepper MS, Gabbiani G, Bochaton-Piallat M-L (2002) Heterogeneity of smooth muscle cell populations cultured from pig coronary artery. Arterioscler Thromb Vasc Biol 22:1093–1099

    Article  CAS  PubMed  Google Scholar 

  • Haond C, Ribreau C, Boutherin-Falson O, Finet M (1999) Laminar flow through a model of collapsed veins. Morphometric response of endothelial vascular cells to a longitudinal shear stress non uniform cross-wise. Eur Phys J Appl Phys 8:87–96

    Article  Google Scholar 

  • Harder DR, Gilbert R, Lombard JH (1987) Vascular muscle cell depolarization and activation in renal arteries on elevation of transmural pressure. Am J Physiol Renal Physiol 253:778–781

    Google Scholar 

  • Harder DR, Narayanan J, Gebremedhin D (2011) Pressure-induced myogenic tone and role of 20-HETE in mediating autoregulation of cerebral blood flow. Am J Physiol Heart Circ Physiol 300:H1557–H1565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrington LS, Mitchell JA (2004) Novel role for P2X receptor activation in endothelium-dependent vasodilation. Br J Pharmacol 143:611–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Helmke BP, Davies PF (2002) The cytoskeleton under external fluid mechanical forces: hemodynamic forces acting on the endothelium. Ann Biomed Eng 30:284–296

    Article  PubMed  Google Scholar 

  • Hendgen-Cotta UB, Merx MW, Shiva S, Schmitz J, Becher S, Klare JP, Steinhoff HJ, Goedecke A, Schrader J, Gladwin MT, Kelm M, Rassaf T (2008) Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl Acad Sci USA 105:10256–10261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herring N, Paterson DJ (2001) Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the guinea-pig in vitro. J Physiol 535:507–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hinson JP, Kapas S, Smith DM (2000) Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev 21:138–167

    CAS  PubMed  Google Scholar 

  • Hoger JH, Ilyin VI, Forsyth S, Hoger A (2002) Shear stress regulates the endothelial Kir2.1 ion channel. Proc Natl Acad Sci USA 99:7780–7785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hou M, Uddman R, Tajti J, Edvinsson L (2003) Nociceptin immunoreactivity and receptor mRNA in the human trigeminal ganglion. Brain Res 964:179–186

    Article  CAS  PubMed  Google Scholar 

  • Hur SS, Del Alamo JC, Park JS, Li YS, Nguyen HA, Teng D, Wang KC, Flores L, Alonso-Latorre B, Lasheras JC, Chien S (2012) Roles of cell confluency and fluid shear in 3-dimensional intracellular forces in endothelial cells. Proc Natl Acad Sci USA 109:11110–11115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue A, Yanagisawa M, Kimura S, Kasuya Y, Miyauchi T, Goto K, Masaki T (1989) The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA 86:2863–2867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoue R, Jian Z, Kawarabayashi Y (2009) Mechanosensitive TRP channels in cardiovascular pathophysiology. Pharmacol Ther 123:371–385

    Article  CAS  PubMed  Google Scholar 

  • Ito H, Hirata Y, Hiroe M, Tsujino M, Adachi S, Takamoto T, Nitta M, Taniguchi K, Marumo F (1991) Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 69:209–215

    Article  CAS  PubMed  Google Scholar 

  • Ivashchenko CY, Bradley BT, Ao Z, Leiper J, Vallance P, Johns DG (2010) Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2. Am J Physiol Heart Circ Physiol 298:H251–H258

    Article  CAS  PubMed  Google Scholar 

  • Jacobs ER, Zeldin DC (2001) The lung HETEs (and EETs) up. Am J Physiol Heart Circ Physiol 280:H1–H10

    CAS  PubMed  Google Scholar 

  • Jankowski V, Tölle M, Vanholder R, Schönfelder G, van der Giet M, Henning L, Schlüter H, Paul M, Zidek W, Jankowski J (2005) Uridine adenosine tetraphosphate: a novel endothelium-derived vasoconstrictive factor. Nat Med 11:223–227

    Article  CAS  PubMed  Google Scholar 

  • Janssen LJ (2001) Isoprostanes: an overview and putative roles in pulmonary pathophysiology. Am J Physiol Lung Cell Mol Physiol 280:L1067–L1082

    CAS  PubMed  Google Scholar 

  • Jin BY, Sartoretto JL, Gladyshev VN, Michel T (2009) Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells. Proc Natl Acad Sci USA 106:17343–17348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson PC (1981) The myogenic response. In: Bohr DF, Somlyo AP, Sparks HV (eds) Vascular smooth muscle. Handbook of physiology. The cardiovascular system. American Physiological Society, Bethesda

    Google Scholar 

  • Karibe A, Watanabe J, Horiguchi S, Takeuchi M, Suzuki S, Funakoshi M, Katoh H, Keitoku M, Satoh S, Shirato K (1997) Role of cytosolic Ca2+ and protein kinase C in developing myogenic contraction in isolated rat small arteries. Am J Physiol Heart Circ Physiol 272:1165–1172

    Google Scholar 

  • Katusic ZS (1996) Superoxide anion and endothelial regulation of arterial tone. Free Radic Biol Med 20:443–448

    Article  CAS  PubMed  Google Scholar 

  • Kauffenstein G, Laher I, Matrougui K, Guérineau NC, Henrion D (2012) Emerging role of G protein-coupled receptors in microvascular myogenic tone. Cardiovasc Res 95:223–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kedzierski RM, Grayburn PA, Kisanuki YY, Williams CS, Hammer RE, Richardson JA, Schneider MD, Yanagisawa M (2003) Cardiomyocyte-specific endothelin A receptor knockout mice have normal cardiac function and an unaltered hypertrophic response to angiotensin II and isoproterenol. Mol Cell Biol 23:8226–8232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelm M, Schrader J (1990) Control of coronary vascular tone by nitric oxide. Circ Res 66:1561–1575

    Article  CAS  PubMed  Google Scholar 

  • Khachigian LM, Resnick N, Gimbrone MA, Collins T (1995) Nuclear factor-kB interacts functionally with the platelet-derived growth factor B-chain shear-stress-response-element in vascular endothelial cells exposed to fluid shear stress. J Clin Invest 96:1169–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King MW (2005) The medical biochemistry page. web.indstate.edu/thcme/mwking

  • Kirber MT, Walsh JV, Singer JJ (1988) Stretch-activated ion channels in smooth muscle: a mechanism for the initiation of stretch-induced contraction. Pflugers Arch 412:339–345

    Article  CAS  PubMed  Google Scholar 

  • Knock GA, Snetkov VA, Shaifta Y, Drndarski S, Ward JP, Aaronson PI (2008) Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery. Cardiovasc Res 80:453–462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knot HJ, Nelson MT (1995) Regulation of membrane potential and diameter by voltage-dependent K+ channels in rabbit myogenic cerebral arteries. Am J Physiol Heart Circ Physiol 269:348–355

    Google Scholar 

  • Kohler R, Grundig A, Brakemeier S, Rothermund L, Distler A, Kreutz R, Hoyer J (2001) Regulation of pressure-activated channel in intact vascular endothelium of stroke-prone spontaneously hypertensive rats. Am J Hypertens 14:716–721

    Article  CAS  PubMed  Google Scholar 

  • Kuchan MJ, Frangos JA (1993) Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol Heart Circ Physiol 264:150–156

    Google Scholar 

  • Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB (2012) The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles. Cardiovasc Res 95:194–204

    Article  CAS  PubMed  Google Scholar 

  • Ledoux J, Taylor MS, Bonev AD, Hannah RM, Solodushko V, Shui B, Tallini Y, Kotlikoff MI, Nelson MT (2008) Functional architecture of inositol 1,4,5-trisphosphate signaling in restricted spaces of myoendothelial projections. Proc Natl Acad Sci USA 105:9627–9632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leffler CW, Parfenova H, Jaggar JH (2011) Carbon monoxide as an endogenous vascular modulator. Am J Physiol Heart Circ Physiol 1:H1–H11

    Article  CAS  Google Scholar 

  • Lehoux S, Tedgui A (2003) Cellular mechanics and gene expression in blood vessels. J Biomech 36:631–643

    Article  PubMed  Google Scholar 

  • Lehoux S, Esposito B, Merval R, Tedgui A (2005) Differential regulation of vascular focal adhesion kinase by steady stretch and pulsatility. Circulation 111:643–649

    Article  CAS  PubMed  Google Scholar 

  • Levonen AL, Patel RP, Brookes P, Go YM, Jo H, Parthasarathy S, Anderson PG, Darley-Usmar VM (2001) Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases. Antioxid Redox Signal 3:215–229

    Article  CAS  PubMed  Google Scholar 

  • Lidington D, Schubert R, Bolz SS (2013) Capitalizing on diversity: an integrative approach towards the multiplicity of cellular mechanisms underlying myogenic responsiveness. Cardiovasc Res 97:404–412

    Article  CAS  PubMed  Google Scholar 

  • Loot AE, Popp R, Fisslthaler B, Vriens J, Nilius B, Fleming I (2008) Role of cytochrome P450-dependent transient receptor potential V4 activation in flow-induced vasodilatation. Cardiovasc Res 80:445–452

    Article  CAS  PubMed  Google Scholar 

  • Luykenaar KD, El-Rahman RA, Walsh MP, Welsh DG (2009) Rho-kinase-mediated suppression of KDR current in cerebral arteries requires an intact actin cytoskeleton. Am J Physiol Heart Circ Physiol 296:H917–H926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma W, Sun Y, Han D, Chu W, Lin D, Chen D (2006) Cytoskeletal response of microvessel endothelial cells to an applied stress force at the submicrometer scale studied by atomic force microscopy. Microsc Res Tech 69:784–793

    Article  PubMed  Google Scholar 

  • Maguire JJ, Davenport AP (2005) Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol Sci 26:448–454

    CAS  PubMed  Google Scholar 

  • Mayr M, Hu Y, Hainaut P, Xu Q (2002) Mechanical stress-induced DNA damage and rac-p38MAPK signal pathways mediate p53-dependent apoptosis in vascular smooth muscle cells. FASEB J 16:1423–1425

    CAS  PubMed  Google Scholar 

  • Mehta D, Malik AB (2006) Signaling mechanisms regulating endothelial permeability. Physiol Rev 86:279–367

    Article  CAS  PubMed  Google Scholar 

  • Meininger GA, Davis MJ (1992) Cellular mechanisms involved in the vascular myogenic response. Am J Physiol Heart Circ Physiol 263:647–659

    Google Scholar 

  • Meng QH, Yang G, Yang W, Jiang B, Wu L, Wang R (2007) Protective effect of hydrogen sulfide on balloon injury-induced neointima hyperplasia in rat carotid arteries. Am J Pathol 170:1406–1414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michaux G, Abbitt KB, Collinson LM, Haberichter SL, Norman KE, Cutler DF (2006) The physiological function of von Willebrand’s factor depends on its tubular storage in endothelial Weibel-Palade bodies. Dev Cell 10:223–232

    Article  CAS  PubMed  Google Scholar 

  • Miller FJ, Dellsperger KC, Guttermann DD (1997) Myogenic constriction of human coronary arterioles. Am J Physiol Heart Circ Physiol 273:H257–H264

    CAS  Google Scholar 

  • Mills I, Letsou G, Rabban J, Sumpio B, Gewirtz H (1990) Mechanosensitive adenylate cyclase activity in coronary vascular smooth muscle cells. Biochem Biophys Res Commun 171:143–147

    Article  CAS  PubMed  Google Scholar 

  • Milner P, Kirkpatrick KA, Ralevic V, Toothill V, Pearson J, Burnstock G (1990) Endothelial cells cultured from human umbilical vein release ATP, substance P and acetylcholine in response to increased flow. Proc R Soc Lond B Biol Sci 241:245–248

    Article  CAS  Google Scholar 

  • Mishra PK, Tyagi N, Sen U, Givvimani SMD, Tyagi SC (2010) H2S ameliorates oxidative and proteolytic stresses and protects the heart against adverse remodeling in chronic heart failure. Am J Physiol Heart Circ Physiol 298:H451–H456

    Article  CAS  PubMed  Google Scholar 

  • Mitchell JD, Maguire JJ, Kuc RE, Davenport AP (2009) Expression and vasoconstrictor function of anorexigenic peptides neuromedin U-25 and S in the human cardiovascular system. Cardiovasc Res 81:353–361

    Article  CAS  PubMed  Google Scholar 

  • Mitrossilis D, Fouchard J, Guiroy A, Desprat N, Rodriguez N, Fabry B, Asnacios A (2009) Single-cell response to stiffness exhibits muscle-like behavior. Proc Natl Acad Sci USA 106:18243–18248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitrossilis D, Fouchard J, Pereira D, Postic F, Richert A, Saint-Jean M, Asnacios A (2010) Real-time single-cell response to stiffness. Proc Natl Acad Sci USA 107:16518–16523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moehlenbrock MJ, Price AK, Martin RS (2006) Use of microchip-based hydrodynamic focusing to measure the deformation-induced release of ATP from erythrocytes. Analyst 131:930–937

    Article  CAS  PubMed  Google Scholar 

  • Mombouli JV, Vanhoutte PM (1997) Endothelium-derived hyperpolarizing factor(s): updating the unknown. Trends Pharmacol Sci 18:252–256

    Article  CAS  PubMed  Google Scholar 

  • Morawietz H, Talanow R, Szibor M, Rueckschloss U, Schubert A, Bartling B, Darmer D, Holtz J (2000) Regulation of the endothelin system by shear stress in human endothelial cells. J Physiol 525:761–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morikawa T, Kajimura M, Nakamura T, Hishiki T, Nakanishi T, Yukutake Y, Nagahata Y, Ishikawa M, Hattori K, Takenouchi T, Takahashi T, Ishii I, Matsubara K, Kabe Y, Uchiyama S, Nagata E, Gadalla MM, Snyder SH, Suematsu M (2012) Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway. Proc Natl Acad Sci USA 109:1293–1298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naili S, Ribreau C (1999) Wall shear stress in collapsed tubes. Eur Phys J Appl Phys 5:95–100

    Article  Google Scholar 

  • Nelson MT, Patlak JB, Worley JF, Standen NB (1990) Calcium channels, potassium channels, and voltage dependence of arterial smooth muscle tone. Am J Physiol Cell Physiol 259:3–18

    Google Scholar 

  • Nelson CP, Rainbow RD, Brignell JL, Perry MD, Willets JM, Davies NW, Standen NB, Challiss RA (2011) Principal role of adenylyl cyclase 6 in K+ channel regulation and vasodilator signalling in vascular smooth muscle cells. Cardiovasc Res 91:694–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nollert MU, Eskin SG, McIntire LV (1990) Shear stress increases inositol trisphosphate levels in human endothelial cells. Biochem Biophys Res Commun 170:281–287

    Article  CAS  PubMed  Google Scholar 

  • Nollert MU, Diamond SL, McIntire LV (1991) Hydrodynamic shear stress and mass transport modulation of endothelial cell metabolism. Biotechnol Bioeng 38:588–602

    Article  CAS  PubMed  Google Scholar 

  • Nyqvist D, Giampietro C, Dejan E (2008) Deciphering the functional role of endothelial junctions by using in vivo models. EMBO Rep 9:742–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogoh S, Ainslie PN, Miyamoto T (2009) Onset responses of ventilation and cerebral blood flow to hypercapnia in humans: rest and exercise. J Appl Physiol 106:880–886

    Article  PubMed  PubMed Central  Google Scholar 

  • Ohno M, Cooke JP, Dzau VJ, Gibbons GH (1995) Fluid shear stress induces endothelial transforming growth factor beta-1 transcription and production. Modulation by potassium channel blockade. J Clin Invest 95:1363–1369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palacios-Callender M, Hollis V, Mitchison M, Frakich N, Unitt D, Moncada S (2007) Cytochrome c oxidase regulates endogenous nitric oxide availability in respiring cells: a possible explanation for hypoxic vasodilation. Proc Natl Acad Sci USA 104:18508–18513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park H, Go YM, St John PL, Maland MC, Lisanti MP, Abrahamson DR, Jo H (1998) Plasma membrane cholesterol is a key molecule in shear stress-dependent activation of extracellular signal-regulated kinase. J Biol Chem 273:32304–32311

    Article  CAS  PubMed  Google Scholar 

  • Park H, Go YM, Darji R, Choi JW, Lisanti MP, Maland MC, Jo H (2000) Caveolin-1 regulates shear stress-dependent activation of extracellular signal-regulated kinase. Am J Physiol Heart Circ Physiol 278:1285–1293

    Google Scholar 

  • Park HS, Yu JW, Cho JH, Kim MS, Huh SH, Ryoo K, Choi EJ (2004) Inhibition of apoptosis signal-regulating kinase 1 by nitric oxide through a thiol redox mechanism. J Biol Chem 279:7584–7590

    Article  CAS  PubMed  Google Scholar 

  • Patel RP, Hogg N, Kim-Shapiro DB (2011) The potential role of the red blood cell in nitrite-dependent regulation of blood flow. Cardiovasc Res 89:507–515

    Article  CAS  PubMed  Google Scholar 

  • Pearce WJ (1995) Mechanisms of hypoxic cerebral vasodilatation. Pharmacol Ther 65:75–91

    Article  CAS  PubMed  Google Scholar 

  • Perrier E, Fournet-Bourguignon MP, Royere E, Molez S, Reure H, Lesage L, Gosgnach W, Frapart Y, Boucher JL, Villeneuve N, Vilaine JP (2009) Effect of uncoupling endothelial nitric oxide synthase on calcium homeostasis in aged porcine endothelial cells. Cardiovasc Res 82:133–142

    Article  CAS  PubMed  Google Scholar 

  • Pieske B, Beyermann B, Breu V, Loffler BM, Schlotthauer K, Maier LS, Schmidt-Schweda S, Just H, Hasenfuss G (1999) Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium. Circulation 99:1802–1809

    Article  CAS  PubMed  Google Scholar 

  • Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, Brunet I, Wan LX, Rey F, Wang T, Firestein SJ, Yanagisawa M, Gordon JI, Eichmann A, Peti-Peterdi J, Caplan MJ (2013) Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci USA 110:4410–4415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poeckel D, Funk CD (2010) The 5-lipoxygenase/leukotriene pathway in preclinical models of cardiovascular disease. Cardiovasc Res 86:243–253

    Article  CAS  PubMed  Google Scholar 

  • Pohl U, Busse R (1989) Hypoxia stimulates release of endothelium-derived relaxant factor. Am J Physiol Heart Circ Physiol 256:1595–1600

    Google Scholar 

  • Pohl U, Holtz J, Busse R, Bassenge E (1986) Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 8:37–44

    Article  CAS  PubMed  Google Scholar 

  • Qin X, Wang X, Wang Y, Tang Z, Cui Q, Xi J, Li YS, Chien S, Wang N (2010) MicroRNA-19a mediates the suppressive effect of laminar flow on cyclin D1 expression in human umbilical vein endothelial cells. Proc Natl Acad Sci USA 107:3240–3244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramiro-Diaz J, Barajas-Espinosa A, Chi-Ahumada E, Perez-Aguilar S, Torres-Tirado D, Castillo-Hernandez J, Knabb M, de Rosa AB, Rubio R (2010) Luminal endothelial lectins with affinity for N-acetylglucosamine determine flow-induced cardiac and vascular paracrine-dependent responses. Am J Physiol Heart Circ Physiol 299:H743–H751

    Article  CAS  PubMed  Google Scholar 

  • Ramzy D, Rao V, Tumiati LC, Xu N, Sheshgiri R, Miriuka S, Delgado DH, Ross HJ (2006) Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway. Circulation 114:I319–I326

    PubMed  Google Scholar 

  • Reichlin T, Wild A, Durrenberger M, Daniels AU, Aebi U, Hunziker PR, Stolz M (2005) Investigating native coronary artery endothelium in situ and in cell culture by scanning force microscopy. J Struct Biol 152:52–63

    Article  PubMed  Google Scholar 

  • Resnick N, Yahav H, Khachigian LM, Collins T, Anderson KR, Dewey FC, Gimbrone MA (1997) Endothelial gene regulation by laminar shear stress. Adv Exp Med Biol 430:155–164

    Article  CAS  PubMed  Google Scholar 

  • Resnick N, Yahav H, Schubert S, Wolfovitz E, Shay A (2000) Signalling pathways in vascular endothelium activated by shear stress: relevance to atherosclerosis. Curr Opin Lipidol 11:167–177

    Article  CAS  PubMed  Google Scholar 

  • Rhodes MA, Carraway MS, Piantadosi CA, Reynolds CM, Cherry AD, Wester TE, Natoli MJ, Massey EW, Moon RE, Suliman HB (2011) Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans. Am J Physiol Heart Circ Physiol 297:H392–H399

    Article  CAS  Google Scholar 

  • Rizvi MA, Katwa L, Spadone DP, Myers PR (1996) The effects of endothelin-1 on collagen type I and type III synthesis in cultured porcine coronary artery vascular smooth muscle cells. J Mol Cell Cardiol 28:243–252

    Article  CAS  PubMed  Google Scholar 

  • Rosenfeld CR, Liu XT, Despain K (2009) Pregnancy modifies the large conductance Ca2+-activated K+ channel and cGMP-dependent signaling pathway in uterine vascular smooth muscle. Am J Physiol Heart Circ Physiol 296:H1878–H1887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salgado MT, Nagababu E, Rifkind JM (2009) Quantification of intermediates formed during the reduction of nitrite by deoxyhemoglobin. J Biol Chem 284:12710–12718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sandow SL (2004) Factors, fiction and endothelium-derived hyperpolarizing factor. Clin Exp Pharmacol Physiol 31:563–570

    Article  CAS  PubMed  Google Scholar 

  • Schnittler HJ, Püschel B, Drenckhahn D (1997) Role of cadherins and plakoglobin in interendothelial adhesion under resting conditions and shear stress. Am J Physiol Heart Circ Physiol 273:H2396–H2405

    CAS  Google Scholar 

  • Schwarz G, Callewaert G, Droogmans G, Nilius B (1992) Shear stress-induced calcium transients in endothelial cells from human umbilical cord veins. J Physiol 458:527–538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Senadheera S, Kim Y, Grayson TH, Toemoe S, Kochukov MY, Abramowitz J, Housley GD, Bertrand RL, Chadha PS, Bertrand PP, Murphy TV, Tare M, Birnbaumer L, Marrelli SP, Sandow SL (2012) Transient receptor potential canonical type 3 channels facilitate endothelium-derived hyperpolarization-mediated resistance artery vasodilator activity. Cardiovasc Res 95:439–447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen J, Luscinskas FW, Connolly A, Dewey CF, Gimbrone MA (1992) Fluid shear stress modulates cytosolic free calcium in vascular endothelial cells. Am J Physiol Cell Physiol 262:384–390

    Google Scholar 

  • Sheng M, McFadden G, Greenberg ME (1990) Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron 4:571–582

    Article  CAS  PubMed  Google Scholar 

  • Shi ZD, Wang H, Tarbell JM (2011) Heparan sulfate proteoglycans mediate interstitial flow mechanotransduction regulating MMP-13 expression and cell motility via FAKERK in 3D collagen. PLoS One 6:e15956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snetkov VA, Smirnov SV, Kua J, Aaronson PI, Ward JP, Knock GA (2011) Superoxide differentially controls pulmonary and systemic vascular tone through multiple signalling pathways. Cardiovasc Res 89:214–224

    Article  CAS  PubMed  Google Scholar 

  • Snyder SH, Ferris CD (2000) Novel neurotransmitters and their neuropsychiatric relevance. Am J Psychiatry 157:1738–1751

    Article  CAS  PubMed  Google Scholar 

  • Sonkusare SK, Bonev AD, Ledoux J, Liedtke W, Kotlikoff MI, Heppner TJ, Hill-Eubanks DC, Nelson MT (2012) Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science 336:597–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spofford CM, Chilian WM (2003) Mechanotransduction via the elastin-laminin receptor (ELR) in resistance arteries. J Biomech 36:645–652

    Article  PubMed  Google Scholar 

  • Sprague RS, Ellsworth ML, Stephenson AH, Kleinhenz ME, Lonigro AJ (1998) Deformation-induced ATP release from red blood cells requires CFTR activity. Am J Physiol Heart Circ Physiol 275:H1726–H1732

    CAS  Google Scholar 

  • Sprague RS, Stephenson AH, Bowles EA, Stumpf MS, Lonigro AJ (2006) Reduced expression of G(i) in erythrocytes of humans with type 2 diabetes is associated with impairment of both cAMP generation and ATP release. Diabetes 55:3588–3593

    Article  CAS  PubMed  Google Scholar 

  • Stamler JS, Jaraki O, Osborne J, Simon DI, Keaney J, Vita J, Singel D, Valeri CR, Loscalzo J (1992) Nitric oxide circulates in mammalian plasma primarily as an Snitroso adduct of serum albumin. Proc Natl Acad Sci USA 89:7674–7677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Storch U, Schnitzler MM, Gudermann T (2012) G protein-mediated stretch reception. Am J Physiol Heart Circ Physiol 302:H1241–H1249

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama T, Michel T (2010) Thiol-metabolizing proteins and endothelial redox state: differential modulation of eNOS and biopterin pathways. Am J Physiol Heart Circ Physiol 298:H194–H201

    Article  CAS  PubMed  Google Scholar 

  • Sun RJ, Muller S, Wang X, Lucius M, Stolz JF (2000) Effect of shear stress on the regulation of von Willebrand factor of human endothelial cells. In: Ribreau C, Berthaud Y, Moreau MR, Ratier L, Renaudaux JP, Thiriet M, Wendling S (eds) Méchanotransduction [Mechanotransduction] 2000. Tec and Doc, Paris

    Google Scholar 

  • Szabó C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6:662–680

    Article  PubMed  CAS  Google Scholar 

  • Takeshita S, Inoue N, Ueyama T, Kawashima S, Yokoyama M (2000) Shear stress enhances glutathione peroxidase expression in endothelial cells. Biochem Biophys Res Commun 273:66–71

    Article  CAS  PubMed  Google Scholar 

  • Tanizawa K (2011) Production of H2S by 3-mercaptopyruvate sulphurtransferase. J Biochem 149:357–359

    Article  CAS  PubMed  Google Scholar 

  • Tarbell JM, Lever MJ, Caro CG (1988) The effect of varying albumin concentration of the hydraulic conductivity of the rabbit common carotid artery. Microvasc Res 35:204–220

    Article  CAS  PubMed  Google Scholar 

  • Thiriet M, Naili S, Ribreau C (2003) Entry length and wall shear stress in uniformly collapsed veins. Comput Model Eng Sci 4:473–488

    Google Scholar 

  • Topper JN, Gimbrone MA (1999) Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype. Mol Med Today 5:40–46

    Article  CAS  PubMed  Google Scholar 

  • Topper JN, Cai J, Falb D, Gimbrone MA (1996) Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. Proc Natl Acad Sci USA 93:10417–10422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Traub O, Ishida T, Ishida M, Tupper JC, Berk BC (1999) Shear stress-mediated extracellular signal-regulated kinase activation is regulated by sodium in endothelial cells. Potential role for a voltage-dependent sodium channel. J Biol Chem 274:20144–20150

    Article  CAS  PubMed  Google Scholar 

  • Trepat X, Deng L, An SS, Navajas D, Tschumperlin DJ, Gerthoffer WYT, Butler JP, Fredberg JJ (2007) Universal physical responses to stretch in the living cell. Nature 447:592–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tzima E, Kiosses WB, del Pozo MA, Schwartz MA (2003a) Localized cdc42 activation, detected using a novel assay, mediates microtubule organizing center positioning in endothelial cells in response to fluid shear stress. J Biol Chem 278:31020–31023

    Article  CAS  PubMed  Google Scholar 

  • Tzima E, Reader JS, Irani-Tehrani M, Ewalt KL, Schwartz MA, Schimmel P (2003b) Biologically active fragment of a human tRNA synthetase inhibits fluid shear stress-activated responses of endothelial cells. Proc Natl Acad Sci USA 100:14903–14907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA (2005a) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431

    Article  CAS  PubMed  Google Scholar 

  • Tzima E, Reader JS, Irani-Tehrani M, Ewalt KL, Schwartz MA, Schimmel P (2005b) VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. J Biol Chem 280:2405–2408

    Article  CAS  PubMed  Google Scholar 

  • Ukropec JA, Hollinger MK, Woolkalis MJ (2002) Regulation of VE-cadherin linkage to the cytoskeleton in endothelial cells exposed to fluid shear stress. Exp Cell Res 273:240–247

    Article  CAS  PubMed  Google Scholar 

  • Urao N, Okigaki M, Yamada H, Aadachi Y, Matsuno K, Matsui A, Matsunaga S, Tateishi K, Nomura T, Takahashi T, Tatsumi T, Matsubara H (2006) Erythropoietin mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia. Cardiovasc Res 98:1405–1413

    CAS  Google Scholar 

  • Urbich C, Dernbach E, Reissner A, Vasa M, Zeiher AM, Dimmeler S (2002) Shear stress-induced endothelial cell migration involves integrin signaling via the fibronectin receptor subunits alpha(5) and beta(1). Arterioscler Thromb Vasc Biol 22:69–75

    Article  CAS  PubMed  Google Scholar 

  • Vanhoutte PM (1997) Endothelial dysfunction and atherosclerosis. Eur Heart J 18:E19–E29

    Article  PubMed  Google Scholar 

  • Vogel V, Sheetz M (2006) Local force and geometry sensing regulate cell functions. Nat Rev Mol Cell Biol 7:265–275

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Fuster M, Sriramarao P, Esko JD (2005) Endothelial heparan sulfate deficiency impairs l-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nat Immunol 6:902–910

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF Jr, Hunt NH, Stocker R (2010a) Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16:279–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang KC, Garmire LX, Young A, Nguyen P, Trinh A, Subramaniam S, Wang N, Shyy JY, Li YS, Chien S (2010b) Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth. Proc Natl Acad Sci USA 107:3234–3239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe T, Kusumoto K, Kitayoshi T, Shimamoto N (1989) Positive inotropic and vasoconstrictive effects of endothelin-1 in in vivo and in vitro experiments: characteristics and the role of L-type calcium channels. J Cardiovasc Pharmacol 13:S108–S111

    Article  CAS  PubMed  Google Scholar 

  • Wei EP, Kontos HA, Beckman JS (1996) Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol Heart Circ Physiol 271:H1262–H1266

    CAS  Google Scholar 

  • White CR, Haidekker MA, Stevens HY, Frangos JA (2004) Extracellular signal-regulated kinase activation and endothelin-1 production in human endothelial cells exposed to vibration. J Physiol 555:565–572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiemer G, Scholkens BA, Becker RH, Busse R (1991) Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin. Hypertension 18:558–563

    Article  CAS  PubMed  Google Scholar 

  • Wiersbitzky M, Mills I, Sumpio BE, Gerwitz H (1994) Chronic cyclic strain reduces adenylate cyclase activity and stimulatory G protein subunit levels in coronary smooth muscle cells. Exp Cell Res 210:52–55

    Article  CAS  PubMed  Google Scholar 

  • Wu CC, Li YS, Haga JH, Kaunas R, Chiu JJ, Su FC, Usami S, Chien S (2007) Directional shear flow and Rho activation prevent the endothelial cell apoptosis induced by micropatterned anisotropic geometry. Proc Natl Acad Sci USA 104:1254–1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie H, Ray PE, Short BL (2005) NF-κB activation plays a role in superoxide-mediated cerebral endothelial dysfunction after hypoxia/reoxygenation. Stroke 36:1047–1052

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Sokabe T, Matsumoto T, Yoshimura K, Shibata M, Ohura N, Fukuda T, Sato T, Sekine K, Kato S, Isshiki M, Fujita T, Kobayashi M, Kawamura K, Kamiya A, Ando J (2005) Impaired flow-dependent control of vascular tone and remodeling in P2X4-deficient mice. Nat Med 12:133–137

    Article  PubMed  CAS  Google Scholar 

  • Yamawaki H, Pan S, Lee RT, Berk BC (2005) Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J Clin Invest 115:733–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Gonon AT, Sjöquist PO, Lundberg JO, Pernow J (2013) Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity. Proc Natl Acad Sci USA 110:15049–15054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin J, Kuebler WM (2010) Mechanotransduction by TRP channels: general concepts and specific role in the vasculature. Cell Biochem Biophys 56:1–18

    Article  CAS  PubMed  Google Scholar 

  • Yong QC, Hu LF, Wang S, Huang D, Bian JS (2010) Hydrogen sulfide interacts with nitric oxide in the heart: possible involvement of nitroxyl. Cardiovasc Res 88:482–491

    Article  CAS  PubMed  Google Scholar 

  • Zhang P, Huang G, Shi X (2011) Cerebral vasoreactivity during hypercapnia is reset by augmented sympathetic influence. J Appl Physiol 110:352–358

    Article  PubMed  Google Scholar 

  • Zou AP, Fleming JT, Falck JR, Jacobs ER, Gebremedhin D, Harder DR, Roman RJ (1996) 20-HETE is an endogenous inhibitor of the large-conductance Ca(2+)-activated K+ channel in renal arterioles. Am J Physiol Regul Integr Comp Physiol 270:228–237

    Google Scholar 

  • Zuckerbraun BS, George P, Gladwin MT (2011) Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovasc Res 89:542–552

    Article  CAS  PubMed  Google Scholar 

Further Reading

  • Chang L, Noseda M, Higginson M, Ly M, Patenaude A, Fuller M, Kyle AH, Minchinton AI, Puri MC, Dumont DJ, Karsan A (2012) Differentiation of vascular smooth muscle cells from local precursors during embryonic and adult arteriogenesis requires Notch signaling. Proc Natl Acad Sci USA 109:6993–6998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demasi M, Laurindo FRM (2012) Physiological and pathological role of the ubiquitin- proteasome system in the vascular smooth muscle cell. Cardiovasc Res 95:183–193

    Article  CAS  PubMed  Google Scholar 

  • Light DB, Capes TL, Gronau RT, Adler MR (1999) Extracellular ATP stimulates volume decrease in Necturus red blood cells. Am J Physiol Cell Physiol 277:C480–C491

    CAS  Google Scholar 

  • Liu WF (2012) Mechanical regulation of cellular phenotype: implications for vascular tissue regeneration. Cardiovasc Res 95:215–222

    Article  CAS  PubMed  Google Scholar 

  • Michel JB, Li Z, Lacolley P (2012) Smooth muscle cells and vascular diseases. Cardiovasc Res 95:135–137

    Article  CAS  PubMed  Google Scholar 

  • Spin JM, Maegdefessel L, Tsao PS (2012) Vascular smooth muscle cell phenotypic plasticity: focus on chromatin remodelling. Cardiovasc Res 95:147–155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sprague RS, Stephenson AH, Ellsworth ML, Keller C, Lonigro AJ (2001) Impaired release of ATP from red blood cells of humans with primary pulmonary hypertension. Exp Biol Med 226:434–439

    CAS  Google Scholar 

  • Sun SG, Zheng B, Han M, Fang XM, Li HX, Miao SB (2011) MiR-146a and Krüppel-like factor 4 form a feedback loop to participate in vascular smooth muscle cell proliferation. EMBO Rep 12:56–62

    Article  CAS  PubMed  Google Scholar 

  • Valente AJ, Yoshida T, Murthy SN, Sakamuri SS, Katsuyama M, Clark RA, Delafontaine P, Chandrasekar B (2012) Angiotensin II enhances AT1-Nox1 binding and stimulates arterial smooth muscle cell migration and proliferation through AT1, Nox1, and interleukin-18. Am J Physiol Heart Circ Physiol 303:H282–H296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science 322:587–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. team INRIA-UPMC-CNRS REO, Laboratoire Jaques-Louis Lions, CNRS UMR 7598, Université Pierre et Marie Curie (Sorbonne Universités), 75252, Paris, Cedex 05, France

    Marc Thiriet

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  1. Division of Cardiovascular Disease Department of Internal Medicine, Health Care Center Bitterfeld, Bitterfeld-Wolfen, Germany

    Peter Lanzer

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Thiriet, M. (2015). Mechanotransduction and Vascular Resistance. In: Lanzer, P. (eds) PanVascular Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-37078-6_258

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