Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension.

Solène Barbeau,Thomas Ducret,Véronique Freund-Michel,Jean-François Quignard,Roger Marthan,Guillaume Gilbert,Pierre Vacher,Guillaume Cardouat,Christelle Guibert,Isabelle Baudrimont

doi:10.3390/biom11091389

Abstract

A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular cells (e.g., contraction, migration, proliferation, production of extracellular matrix proteins, etc.) depend on a key event, i.e., the increase in intracellular calcium concentration ([Ca2+]i) which results from an influx of extracellular Ca2+ and/or a release of intracellular stored Ca2+. Calcium entry from the extracellular space is a major step in the elevation of [Ca2+]i, involving a variety of plasmalemmal Ca2+ channels including the superfamily of stretch-activated channels (SAC). A common characteristic of SAC is that their gating depends on membrane stretch. In general, SAC are non-selective Ca2+-permeable cation channels, including proteins of the TRP (Transient Receptor Potential) and Piezo channel superfamily. As membrane mechano-transducers, SAC convert physical forces into biological signals and hence into a cell response. Consequently, SAC play a major role in pulmonary arterial calcium homeostasis and, thus, appear as potential novel drug targets for a better management of PH.

Highlights

Pulmonary arteries (PA) are continually subjected to mechanical forces exerted by circulating blood on the three-layered vessel wall(Figure 1)
pulmonary hypertension (PH) is divided into five groups according to clinical, hemodynamic, etiological characteristics, and treatment strategy: idiopathic and heritable pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to lung diseases and/or hypoxia, PH associated to chronic thromboembolism, and PH forms with unclear or multifaceted origins [4]
Transient Receptor Potential (TRP) channels constitute a superfamily of non-selective cationic channels (Table 1) that exhibit a common structure composed of N- and C-terminal regions containing protein interaction motifs and six transmembrane domains (TM1-TM6)

Summary

Introduction

Pulmonary arteries (PA) are continually subjected to mechanical forces exerted by circulating blood on the three-layered vessel wall (i.e., intima, media, and adventitia). PH is divided into five groups according to clinical, hemodynamic, etiological characteristics, and treatment strategy: idiopathic and heritable pulmonary arterial hypertension (PAH) (group 1), PH due to left heart disease (group 2), PH due to lung diseases and/or hypoxia (group 3), PH associated to chronic thromboembolism (group 4), and PH forms with unclear or multifaceted origins (group 5) [4] This is accompanied by an alteration of mechanical stresses to the vessel wall: an increased myogenic tone [6], a reduced flow rate [7] that is responsible for a lower shear stress [8], and a progressive PA stiffening [3]. Many mechanosensitive cellular components and extracellular structures have been shown to contribute to mechanotransduction [10], in PA wall in particular, the scope of this review is deliberately limited to SAC activation

Stretch-Activated Channels

TRP Channels

Piezo Channels

Other Mechanosensitive Channels

Findings

Conclusions