Hypoxia-Induced Pulmonary Vascular Remodeling

Abstract

Abstract-Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site-and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.

Pulmonary vascular changes in asthma and COPD

“…Changes in VEGF expression together with hypoxia has been shown to be important in the onset of vascular remodelling [123], and may have an important role in the pathophysiology of COPD. Basic FGF and VEGF are key mediators in angiogenesis processes in the airways and promote proliferation of endothelial cells in vitro [124] and may therefore have a central role in angiogenesis in COPD.…”

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats

“…In the current study, we noted a significant increase in the percentage of proliferating α-SMA-positive cells in the pulmonary vascular medial wall on exposure to hyperoxia. These α-SMA-positive cells may originate from the proliferation of resident vascular smooth muscle cells, adventitial fibroblasts, recruitment of vascular progenitors cells, and transition of endothelial cells into a mesenchymal phenotype (32)(33)(34)(35). Inhibition of LRP5/6 during hyperoxia resulted in a decrease in the percentage of proliferating α-SMA cells in the pulmonary vascular medial wall.…”

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

“…98 Given that extension of smooth muscle into the distal pulmonary vasculature is the hallmark of hypoxia-induced remodeling, substantial focus has been placed on the growth and survival responses of PASMCs to hypoxia. Although the proliferative response is still not completely understood, it is clearly complex, involving a multiplicity of pathways.…”