Remodeling Matrix Synthesis in a Rat Model of Aortocaval Fistula and the Cyclic Stretch: Impaction in Pulmonary Arterial Hypertension-Congenital Heart Disease.

Chi-Jen Chang,Ying-Ju Lai,Po-Ru Chen,Chung-Chi Huang

doi:10.3390/ijms21134676

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).

Highlights

The pulmonary circulation is a relatively low pressure system compared to the systemic circulation because the pulmonary arteries (PAs) are not as muscularized as their systemic counterparts
The findings showed that the PAs of patients with pulmonary arterial hypertension-congenital heart disease (PAH-congenital heart disease (CHD)) were characterized by collagen accumulation and elastic laminae degradation in the medial and adventitial layers
It is of interest to profile the downstream target factors due to the dynamic volume-overload stretch effect in the extracellular matrix (ECM) assembly of vascular smooth muscle cell (SMC) under investigation to clarify the pathology of PAH-CHD

Summary

Introduction

The pulmonary circulation is a relatively low pressure system (approximately 14 mm Hg at rest) compared to the systemic circulation (approximately 100 mmHg at rest) because the pulmonary arteries (PAs) are not as muscularized as their systemic counterparts. More than 90% of these patients are subjected to percutaneous or surgical repair early in life for a simple, noninvasive diagnostic evaluation [1,2] In these instances, the clinical history, physical examination, chest X-ray, and echocardiographic analysis show features of a typical hyperkinetic pulmonary circulation associated with congestive heart failure, pulmonary congestion, and failure to thrive [3,4]. A probable 5%–10% of patients do not present with these features, even in the presence of unrestricted communications [2,3,4,5] These patients are commonly subjected to invasive diagnostic examination (cardiac catheterization) prior to surgery, and a pulmonary vascular resistance (PVR) above 3 Wood units is detected as pulmonary arterial hypertension-congenital heart disease (PAH-CHD) [2,3]. 100% of unoperated patients with volume overload develop pulmonary hypertension (PH) [2,3,6]

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