Abstract
Pulmonary arterial hypertension-congenital heart disease (PAH-CHD) is characterized by systemic to pulmonary arterial shunts and sensitively responds to volume overload and stretch of the vascular wall leading to pulmonary vascular remodeling. We hypothesized that the responses of pulmonary artery smooth muscle cells (PASMCs) to mechanical stress-associated volume overload may promote vascular remodeling in PAH-CHD. Here, we show that significantly increased collagen was in the PA adventitial layer by trichrome staining in PAH-CHD patients and an aortocaval fistula (ACF) rat model in which chronic vascular volume overload induced-PAH. We assessed the gene expression profiles of SMC markers, extracellular matrix, and collagen in isolated SMCs from pulmonary and thoracic vessels with cyclic stretch-triggered responses by real-time PCR analysis. The data corresponded to collagen deposition, which modulated pulmonary vascular remodeling in clinical and experimental PAH-ACF cases as well as in cyclic stretch-triggered SMCs in an in vitro model. We observe that collagen I A2 (COLIA2) is expressed in the control rat, but collagen I A1 (COLIA1) and Notchs remarkably increase in the lungs of ACF rats. Interestingly, closing the left-to-right shunt that leads to a reduced blood volume in the PA system of ACF rats (ACFRs) decreased the expression of COLIA1 and increased that of collagen I A2(COLIA2). This study contributes to the stretch-induced responses of SMCs and provides important future directions for therapies aimed at preventing abnormal matrix protein synthesis in volume overload-induced pulmonary hypertension (PH).