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Altered integrin expression in hypoxic pulmonary hypertension

Exposure to chronic hypoxia causes pulmonary vascular remodeling resulting in hypoxic pulmonary hypertension. Pulmonary vascular remodeling is accompanied by increased deposition of extracellular matrix (ECM) components, resulting in medial and adventitial thickening. Interaction of ECM proteins with receptors, or integrins, activate intracellular signal transduction including those mediated by intracellular calcium ([Ca2+]i). Despite allusions made as to the participation of the ECM in the progression of pulmonary hypertension, direct evidence supporting this notion is scant. We therefore explored the role of integrins in the pulmonary vasculature, and examined (1) integrin‐mediated [Ca2+]i signaling in pulmonary arterial smooth muscle cells (PASMCs) isolated from normoxic rats, and (2) changes in integrin expression in rat intralobar PASM upon exposure to chronic hypoxia. Our data indicate that integrin ligation indeed alters [Ca2+]i homeostasis in PASMCs, mobilizing [Ca2+]i equally from ryanodine receptor‐gated [Ca2+]i stores and lysosome‐like acidic organelles that are modulated by NAADP. In addition, immunoblots show dramatic upregulation of integrins α5 and β 1, and to a lesser extent αv and β 3, in intralobar PASM challenged with chronic hypoxia. Integrin levels in the systemic vasculature were unaffected, as seen by immunoblots with aortic smooth muscle. These data collectively substantiate our hypothesis that integrin signaling plays important roles in regulating pulmonary function, and may have profound consequences in pulmonary hypertension. (PHA fellowship‐ AU; HL075134 /HL071835‐ JSKS)