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Pulmonary Hypertension: Pathophysiology and Signaling Pathways

  • Chapter
  • First Online:
Pharmacotherapy of Pulmonary Hypertension

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

Pulmonary hypertension (PH) is characterized by pathological changes to cell signaling pathways within the alveolar-pulmonary arteriole–right ventricular axis that results in increases in pulmonary vascular resistance and, ultimately, the development of right ventricular (RV) dysfunction. Cornerstone histopathological features of the PH vasculopathy include intimal thickening, concentric hypertrophy, and perivascular fibrosis of distal pulmonary arterioles. The presence of plexogenic lesions is pathognomonic of pulmonary arterial hypertension (PAH); when present, this severe form of remodeling is associated with subtotal obliteration of the blood vessel lumen. The extent of RV remodeling in PH correlates with clinical symptom severity and portends a poor outcome. Currently available PH-specific pharmacotherapies that aim to improve symptom burden by targeting pulmonary vasodilatory/vasoconstrictor cell signaling pathways do not fully reverse pulmonary vascular remodeling and, thus, are largely unsuccessful at maintaining normal cardiopulmonary hemodynamics long term. Thus, determining the molecular mechanisms that are responsible for pulmonary vascular remodeling in PH is of great potential therapeutic value, particularly pathways that promote apoptosis-resistant cellular proliferation, disrupt normal cellular bioenergetics to alter cell function, and/or modulate severely abnormal responses to pulmonary vascular injury. This chapter reviews current insights into PH pathophysiology and disease mechanisms, and discusses novel cell signaling pathways that implicate microRNAs and mitochondrial dysfunction in the development of the PH phenotype.

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Notes

  1. 1.

    GAF is an acronym of the various tissues in which these domains were originally described: cGMP-dependent phosphodiesterases (PDEs), nabaena adenylyl cyclases, and E. coli FhlA (Francis et al. 2010).

Abbreviations

BH4 :

Tetrahydrobiopterin

BMP-RII:

Bone morphogenetic protein receptor II

cAMP:

Cyclic adenosine monophosphate

cGMP:

Cyclic guanosine monophosphate

COX:

Cyclooxygenase

EGFR:

Epidermal growth factor receptor

eNOS:

Endothelial nitric oxide synthase

ET-1:

Endothelin-1

ETA :

Endothelin-type A receptor

ETB :

Endothelin-type B receptor

FeNO:

Iron-nitrosyl

GTP:

Guanosine triphosphate

HAPE:

High altitude pulmonary edema syndrome

HHT:

Hereditary hemorrhagic telangiectasia

HIF:

Hypoxia-inducible factor

HIV:

Human immunodeficiency virus

IL:

Interleukin

ISCU1/2:

Iron–sulfur cluster assembly proteins

KL:

Kruppel-like factor

LO:

Lipooxygenases

LV:

Left ventricle

MAPK:

Mitogen-activated protein kinase

miR:

MicroRNA

NO• :

Nitric oxide

NOX:

NADPH oxidase

•O2 − :

Superoxide

O2NOO− :

Peroxynitrate

ONOO− :

Peroxynitrite

PAEC:

Pulmonary artery endothelial cells

PAH:

Pulmonary arterial hypertension

PDE:

Phosphodiesterase inhibitor

PDGF:

Platelet-derived growth factor

PDK:

Pyruvate dehydrogenase kinase

PG:

Prostaglandin

PH:

Pulmonary hypertension

PKG:

Protein kinase G

PPAR-γ:

Peroxisome proliferator-activated receptor

PSMC:

Pulmonary artery smooth muscle cells

PTPC:

Permeability transition pore complex

ROS:

Reactive oxygen species

RV:

Right ventricle

sGC:

Soluble guanylyl cyclase

SOD:

Superoxide dismutase

TAPSE:

Tricuspid annular plane systolic excursion

TGF:

Transforming growth factor

TXA2 :

Thromboxane

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB Room 0630-AO, Boston, MA, 02115, USA

    Bradley A. Maron & Joseph Loscalzo

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  1. Bradley A. Maron
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  2. Joseph Loscalzo
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Correspondence to Joseph Loscalzo .

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Editors and Affiliations

  1. Faculte´ de Me´decine, Univ Paris-Sud, Le Kremlin Bicêtre, France

    Marc Humbert

  2. Dep of Anasthesia and Critical Care, Harvard Medical School Massachusetts General Hospital, Boston, Massachusetts, USA

    Oleg V. Evgenov

  3. Cardiovascular Research, Bayer Pharma AG, Wuppertal, Germany

    Johannes-Peter Stasch

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Maron, B.A., Loscalzo, J. (2013). Pulmonary Hypertension: Pathophysiology and Signaling Pathways. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_2

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