Osteopontin, a Key Mediator Expressed by Senescent Pulmonary Vascular Cells in Pulmonary Hypertension

Abstract

Objective-Senescent pulmonary artery smooth muscle cells (PA-SMCs) may contribute to the pathogenesis of pulmonary hypertension by producing secreted factors. The aim of this study was to explore the role in pulmonary hypertension of extracellular matrix proteins released by senescent PA-SMCs. Approach and Results-Polymerase chain reaction array analysis of human PA-SMCs undergoing replicative senescence revealed osteopontin upregulation, which mediated the stimulatory effect of senescent PA-SMC media and matrix on PA-SMC growth and migration. Osteopontin was upregulated in lungs from patients with chronic obstructive pulmonary disease or idiopathic pulmonary arterial hypertension. Prominent osteopontin immunostaining was noted in PASMCs that also stained for p16 at sites of vascular hypertrophy, and lung osteopontin levels correlated closely with age. Compared with younger mice, 1-year-old mice displayed higher lung osteopontin levels, right ventricular systolic pressure, pulmonary vessel muscularization, and numbers of PA-SMCs stained for p16 or p21 and also for osteopontin.No such changes with age were observed in osteopontin −/− mice, which developed attenuated pulmonary hypertension during hypoxia. Compared with cultured PA-SMCs from young mice, PA-SMCs from 1-year-old mice grew faster; a similar fast growth rate was seen with PA-SMCs from young mice stimulated by matrix or media from old mice. Differences between old/young mouse PA-SMC growth rates were suppressed by antiosteopontin antibodies. PA-SMCs from osteopontin −/− mice grew more slowly than did wild-type PA-SMCs; they were stimulated by wild-type PA-SMCs media and matrix, and this effect was stronger with PA-SMCs from older versus younger mice. Conclusions-Osteopontin is a key mediator released by senescent PA-SMCs and contributing to pulmonary hypertension progression.

Osteopontin plays important roles in pulmonary arterial hypertension induced by systemic‐to‐pulmonary shunt

“…4 and 5, OPN levels were elevated in proliferating PASMCs as compared with quiescent PASMCs, and OPN promoted PASMC proliferation and migration in dose-and time-dependent manners, whereas antagonizing OPN with neutralizing antibody (LM609) or selective RGD peptide antagonist (XJ735) significantly inhibited and even abolished PASMC proliferation and migration, indicating the reciprocal cause-effect relationship between OPN increase in hypertensive lungs and the advancement of PAH induced by systemicto-pulmonary shunts. This is consistent with a recent study by Saker et al (5), which also confirmed that PASMC-derived OPN stimulates growth and migration of PASMCs. Furthermore, studies have also confirmed that Akt and ERK1/2 signaling pathways were involved in the proliferation and migration of systemic VSMCs and pulmonary adventitial fibroblasts (6,(30)(31)(32).…”

“…1 and 2). This is in accordance with a previous report confirming that OPN was up-regulated in lungs from patients with chronic obstructive pulmonary disease or idiopathic PAH (5). Actually, OPN could be induced in response to pressure or volume overload in systemic arteries (26,27); however, little is known about the expression pattern of OPN in lungs of CHD/PAH suffering volume and pressure overload.…”

“…Recent studies indicated that osteopontin (OPN) is an essential contributor to the activated phenotype of PASMCs (highly proliferative, migratory) and pulmonary adventitial fibroblasts in hypoxic PAH (5,6). OPN could be induced in response to pressure or volume overload in systemic arteries.…”

“…Interestingly, OPN is seldom expressed in normal systemic arteries but is abundant in injured systemic arteries (7,8), and re-expressed OPN serves as an inducer of vascular smooth muscle cell (VSMC) proliferation and migration (9,10) and thus contributes to medial thickness and neointimal formation after systemic artery injury (8,11). Furthermore, OPN gene knockout (5,12) or blocking of its receptor anb3-integrin could attenuate or abolish neointimal formation (13)(14)(15), implicating the involvement of OPN in the pathogenesis of vascular remodeling; however, no report has focused on the role of OPN in pulmonary vascular remodeling of CHD/PAH. Phenotypical modification of VSMCs is a common event between systemic vascular remodeling and pulmonary vascular remodeling, and the parallel data from systemic vascular remodeling may have some meaning in dealing with the dilemma of PAH.…”

The Role of Transient Receptor Potential Channel 6 Channels in the Pulmonary Vasculature

“…In contrast, other authors have demonstrated attenuation of PH and pulmonary vascular remodeling in TRPC6 KO mice after 4 weeks of hypoxia (43). Although the exact reason is not clear, differences in age (44, 45), gender (46), strain, and substrain (47, 48) of mice can account for most of the discrepancies.…”