Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Captopril treatment during development alleviates mechanically induced aortic remodeling in newborn elastin knockout mice

  • 123 Accesses


Deposition of elastin and collagen in the aorta correlates with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical properties in response to hemodynamic stresses. Elastin knockout (Eln/) mice have high blood pressure and pathological remodeling of the aorta and die soon after birth. We hypothesized that decreasing blood pressure in Eln/ mice during development may reduce hemodynamic stresses and alleviate pathological remodeling of the aorta. We treated Eln+/+ and Eln/ mice with the anti-hypertensive medication captopril throughout embryonic development and then evaluated left ventricular (LV) pressure and aortic remodeling at birth. We found that captopril treatment decreased Eln/ LV pressure to values near Eln+/+ mice and alleviated the wall thickening and changes in mechanical behavior observed in untreated Eln/ aorta. The changes in thickness and mechanical behavior in captopril-treated Eln/ aorta were not due to alterations in measured elastin or collagen amounts, but may have been caused by alterations in smooth muscle cell (SMC) properties. We used a constitutive model to understand how changes in stress contributions of each wall component could explain the observed changes in composite mechanical behavior. Our modeling results show that alterations in the collagen natural configuration and SMC properties in the absence of elastin may explain untreated Eln/ aortic behavior and that partial rescue of the SMC properties may account for captopril-treated Eln/ aortic behavior.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9


  1. Aars H (1971) Effects of altered smooth muscle tone on aortic diameter and aortic baroreceptor activity in anesthetized rabbits. Circ Res 28:254–262

  2. Amin M, Kunkel AG, Le VP, Wagenseil JE (2011) Effect of storage duration on the mechanical behavior of mouse carotid artery. J Biomech Eng 133:071007.

  3. Ben Driss A, Benessiano J, Poitevin P, Levy BI, Michel JB (1997) Arterial expansive remodeling induced by high flow rates. Am J Physiol 272:H851–858

  4. Bouchireb K et al (2010) Clinical features and management of arterial hypertension in children with Williams–Beuren syndrome. Nephrol Dial Transplant 25:434–438.

  5. Burson JM, Aguilera G, Gross KW, Sigmund CD (1994) Differential expression of angiotensin receptor 1A and 1B in mouse. Am J Physiol 267:E260–E267.

  6. Cheng JK, Wagenseil JE (2012) Extracellular matrix and the mechanics of large artery development. Biomech Model Mechanobiol.

  7. Cheng JK, Stoilov I, Mecham RP, Wagenseil JE (2013) A fiber-based constitutive model predicts changes in amount and organization of matrix proteins with development and disease in the mouse aorta. Biomech Model Mechanobiol 12:497–510.

  8. Chuong CJ, Fung YC (1986) On residual stresses in arteries. J Biomech Eng 108:189–192

  9. Clark ER (1918) Studies on the growth of blood-vessels in the tail of the frog larva—by observation and experiment on the living animal American. J Anat 23:37–88

  10. Cocciolone AJ, Johnson E, Shao JY, Wagenseil JE (2018) Elastic fiber fragmentation increases transmural hydraulic conductance and solute transport in mouse arteries. J Biomech Eng.

  11. Davis EC (1995) Elastic lamina growth in the developing mouse aorta. J Histochem Cytochem 43:1115–1123

  12. Davis NP, Han HC, Wayman B, Vito R (2005) Sustained axial loading lengthens arteries in organ culture. Ann Biomed Eng 33:867–877

  13. Espinosa MG, Gardner WS, Bennett L, Sather B, Yanagisawa H, Wagenseil JE (2013) The effects of elastic fiber protein insufficiency and treatment on the modulus of arterial smooth muscle cells. J Biomech Eng.

  14. Espinosa MG, Taber LA, Wagenseil JE (2018) Reduced embryonic blood flow impacts extracellular matrix deposition in the maturing aorta. Dev Dyn.

  15. Faury G, Maher GM, Li DY, Keating MT, Mecham RP, Boyle WA (1999) Relation between outer and luminal diameter in cannulated arteries. Am J Physiol 277:H1745–1753

  16. Faury G et al (2003) Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency. J Clin Invest 112:1419–1428

  17. Ferruzzi J, Vorp DA, Humphrey JD (2011) On constitutive descriptors of the biaxial mechanical behaviour of human abdominal aorta and aneurysms. J R Soc Interface 8:435–450.

  18. Fonck E, Prod’hom G, Roy S, Augsburger L, Rufenacht DA, Stergiopulos N (2007) Effect of elastin degradation on carotid wall mechanics as assessed by a constituent-based biomechanical model. Am J Physiol Heart Circ Physiol 292:H2754–2763.

  19. Fritze O et al (2012) Age-related changes in the elastic tissue of the human aorta. J Vasc Res 49:77–86.

  20. Gerrity RG, Cliff WJ (1975) The aortic tunica media of the developing rat. I. Quantitative stereologic and biochemical analysis. Lab Invest 32:585–600

  21. Gleason RL, Taber LA, Humphrey JD (2004) A 2-D model of flow-induced alterations in the geometry, structure and properties of carotid arteries. J Biomech Eng 126:371–381

  22. Habashi JP et al (2011) Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism. Science 332:361–365.

  23. Huang J et al (2013) Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice. Sci Transl Med 5:183ra158, 181–111.

  24. Humphrey JD, Rajagopal KR (2002) A constrained mixture model for growth and remodeling of soft tissues. Math Models Method Appl Sci 12:407–430

  25. Humphrey JD, Milewicz DM, Tellides G, Schwartz MA (2014) Cell biology: dysfunctional mechanosensing in aneurysms. Science 344:477–479.

  26. Jamall IS, Finelli VN, Que Hee SS (1981) A simple method to determine nanogram levels of 4-hydroxyproline in biological tissues. Anal Biochem 112:70–75

  27. Karnik SK et al (2003) A critical role for elastin signaling in vascular morphogenesis and disease. Development 130:411–423

  28. Kelleher CM, McLean SE, Mecham RP (2004) Vascular extracellular matrix and aortic development. Curr Top Dev Biol 62:153–188

  29. Kim J, Procknow JD, Yanagisawa H, Wagenseil JE (2015) Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice. Am J Physiol Heart Circ Physiol. 309:H103–H113.

  30. Kim J, Staiculescu MC, Cocciolone AJ, Yanagisawa H, Mecham RP, Wagenseil JE (2017) Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. J Biomech 61:199–207.

  31. Knutsen R et al (2018) Minoxidil improves vascular compliance, restores cerebral blood flow and alters extracellular matrix gene expression in a model of chronic vascular stiffness. Am J Physiol Heart Circ Physiol.

  32. Kozel BA et al (2014) Williams syndrome predisposes to vascular stiffness modified by antihypertensive use and copy number changes in NCF1. Hypertension 63:74–79.

  33. Langille BL (1993) Remodeling of developing and mature arteries: endothelium, smooth muscle, and matrix. J Cardiovasc Pharmacol 21(Suppl 1):S11–S17

  34. Le VP, Kovacs A, Wagenseil JE (2012) Measuring left ventricular pressure in late embryonic and neonatal mice. J Vis Exp JoVE.

  35. Leung DY, Glagov S, Mathews MB (1977) Elastin and collagen accumulation in rabbit ascending aorta and pulmonary trunk during postnatal growth. Correlation of cellular synthetic response with medial tension. Circ Res 41:316–323

  36. Li DY, Toland AE, Boak BB, Atkinson DL, Ensing GJ, Morris CA, Keating MT (1997) Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet 6:1021–1028

  37. Li DY et al (1998) Elastin is an essential determinant of arterial morphogenesis. Nature 393:276–280

  38. Liu SQ, Fung YC (1989) Relationship between hypertension, hypertrophy, and opening angle of zero-stress state of arteries following aortic constriction. J Biomech Eng 111:325–335

  39. Niklason LE, Gao J, Abbott WM, Hirschi KK, Houser S, Marini R, Langer R (1999) Functional arteries grown in vitro. Science 284:489–493

  40. Osei-Owusu P, Knutsen RH, Kozel BA, Dietrich HH, Blumer KJ, Mecham RP (2014) Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency. Am J Physiol Heart Circ Physiol 306:H654–666.

  41. Pober B, Johnson M, Urban Z (2008) Mechanisms and treatment of cardiovascular disease in Williams–Beuren syndrome. J Clin Invest 118:1606–1615.

  42. Rachev A, Shazly T (2019) A structure-based constitutive model of arterial tissue considering individual natural configurations of elastin and collagen. J Mech Behav Biomed Mater 90:61–72.

  43. Rensen SSM, Doevendans PAFM, van Eys GJJM (2007) Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J 15:100–108

  44. Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182:311–322.;2-9

  45. Staiculescu MC, Kim J, Mecham RP, Wagenseil J (2017) Mechanical behavior and matrisome gene expression in aneurysm-prone thoracic aorta of newborn lysyl oxidase knockout mice. Am J Physiol Heart Circ Physiol 00712:02016.

  46. Staiculescu MC, Cocciolone A, Procknow J, Kim J, Wagenseil JE (2018) Comparative gene array analyses of severe elastic fiber defects in late embryonic and newborn mouse aorta. Physiol Genom.

  47. Starcher B (2001) A ninhydrin-based assay to quantitate the total protein content of tissue samples. Anal Biochem 292:125–129.

  48. Stoka KV, Maedeker JA, Bennett L, Bhayani SA, Gardner WS, Procknow JD, Cocciolone AJ, Walji TA, Craft CS, Wagenseil JE (2018) Effects of increased arterial stiffness on atherosclerotic plaque amounts. J Biomech Eng.

  49. Wagenseil JE (2011) A constrained mixture model for developing mouse aorta. Biomech Model Mechanobiol 10:671–687.

  50. Wagenseil JE, Mecham RP (2009) Vascular extracellular matrix and arterial mechanics. Physiol Rev 89:957–989.

  51. Wagenseil JE, Ciliberto CH, Knutsen RH, Levy MA, Kovacs A, Mecham RP (2009) Reduced vessel elasticity alters cardiovascular structure and function in newborn mice. Circ Res 104:1217–1224.

  52. Wagenseil JE, Ciliberto CH, Knutsen RH, Levy MA, Kovacs A, Mecham RP (2010) The importance of elastin to aortic development in mice. Am J Physiol Heart Circ Physiol 299:H257–264.

  53. Wessel A, Pankau R, Kececioglu D, Ruschewski W, Bursch JH (1994) Three decades of follow-up of aortic and pulmonary vascular lesions in the Williams–Beuren syndrome. Am J Med Genet 52:297–301.

  54. Wolinsky H (1970) Response of the rat aortic media to hypertension: morphological and chemical studies. Circ Res 26:507–522

Download references


This study was partially funded by NSF Grant 1662434 (J. Wagenseil), NIH Grants HL-115560 (J. Wagenseil), HL-53325 (R. Mecham), and HL-105314 (R. Mecham and J. Wagenseil).

Author information

Correspondence to Jessica E. Wagenseil.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, J., Cocciolone, A.J., Staiculescu, M.C. et al. Captopril treatment during development alleviates mechanically induced aortic remodeling in newborn elastin knockout mice. Biomech Model Mechanobiol 19, 99–112 (2020).

Download citation


  • Elastin
  • Extracellular matrix
  • Arterial mechanics
  • Arterial development
  • Arterial remodeling
  • Captopril
  • Angiotensin-converting enzyme
  • Angiotensin II