Molecular Mechanisms of Pulmonary Arterial Remodeling

Abstract

Pulmonary arterial hypertension (PAH) is characterized by a persistent elevation of pulmonary arterial pressure and pulmonary arterial remodeling with unknown etiology. Current therapeutics available for PAH are primarily directed at reducing the pulmonary blood pressure through their effects on the endothelium. It is well accepted that pulmonary arterial remodeling is primarily due to excessive pulmonary arterial smooth muscle cell (PASMC) proliferation that leads to narrowing or occlusion of the pulmonary vessels. Future effective therapeutics will be successful in reversing the vascular remodeling in the pulmonary arteries and arterioles. The purpose of this review is to provide updated information on molecular mechanisms involved in pulmonary arterial remodeling with a focus on growth factors, transcription factors, and epigenetic pathways in PASMC proliferation. In addition, this review will highlight novel therapeutic strategies for potentially reversing PASMC proliferation.

Contemporary diagnosis and management of pulmonary hypertension

“…Due to space constraints, it is not possible to describe in detail the signalling pathways thought to play a key role in the pathobiology of PAH, but this has been reviewed 40 41. The process of pulmonary vascular remodelling involves all layers of the vessel wall.…”

NADPH Oxidase 4 Is Expressed in Pulmonary Artery Adventitia and Contributes to Hypertensive Vascular Remodeling

“…PH is resistant to current therapies and is characterized by excessive vascular cell proliferation, inward remodeling, rarefaction and a loss of compliance of the pulmonary blood vessels 1–3 . Increased resistance to blood flow and more rigid blood vessels leads to failure of the right ventricle and eventual death.…”

Platelet TLR4

“…Hypoxia also increased serum levels of serotonin in WT mice 13 which is known to be involved in the pathogenesis of PAH. 1 The upregulation of serum levels of serotonin was abrogated by platelet-specific deletion of TLR4, suggesting that the platelets are the primary source of the hypoxia-induced increase in circulating serotonin. Although it is known that TLR4 is involved in the pathogenesis of PAH, this study further specified a critical role of the platelet TLR4 in the development of experimental PAH.…”

“…1 Among them, PDGF is an extremely potent mitogen and chemoattractant for PASMCs. 2 The PDGF level and its receptor expression are elevated in PASMCs in animal models of PAH.…”

“…5 Multiple experimental studies support a role of PDGF in the pathogenesis of PAH. 1 Inhibition of PDGF by imatinib (or Gleevec) was able to reverse pulmonary hypertension in two different animal models of PAH. 6 Imatinib improved pulmonary arterial remodeling, right ventricular hypertrophy and cardiac output and increased animal survival.…”