Vascular remodeling in pulmonary hypertension

Abstract

Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions, and the appearance of cells expressing smooth muscle-specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular transdifferentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase, and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting.

Fig. 1

Some of the proposed signaling mechanisms in pulmonary arterial smooth muscle cells (PASMCs) leading to vascular remodeling during pulmonary hypertension. Agonists, including endothelin-1 (ET-1), bone morphogenetic proteins 2 and 4 (BMP2 and BMP4, respectively) and serotonin (5-HT) interact with membrane bound receptors or transporters (serotonin transporter, SERT). Activation of ET-1 receptors leads to increased intracellular K⁺ concentration and inhibition of apoptosis, as well as activation of Rho kinase (ROCK) and downstream signaling through activation of the Na⁺/H⁺ exchanger (NHE) and elevation of intracellular Ca²⁺. NHE increases ROCK activation and promotes migration and proliferation via downregulation of p27 and activation of the transcription factor E2F1. NHE has also been found to increase ROCK, suggesting potential feed-forward regulation. BMP4 and 5-HT both increase intracellular Ca²⁺, which is required for PASMC migration and proliferation. 5-HT-induced ROCK activity also leads to PASMC proliferation; whether this involves modulation of Ca²⁺ or Ca²⁺-independent pathways is unclear. BMP2 binding to type 1 and type 2 receptors (BMPR1 and BMPR2) activates SMAD1/5/8 signaling and represses proliferation and stimulates apoptosis. Pharmacological inhibitors (in red) reduce vascular remodeling by disrupting signaling at various points.

Fig. 2

Hypoxia-inducible factor 1 (HIF-1) and pulmonary arterial smooth muscle responses during pulmonary hypertension. Exposure to hypoxia or growth factors activates HIF-1, leading to upregulation of endothelin-1 (ET-1), canonical transient receptor potential (TRPPC) proteins and Na⁺/H⁺ exchanger isoform 1 (NHE1). Elevated ET-1 levels reduce K⁺ channel expression and activity, allowing intracellular accumulation of K⁺ and repression of apoptosis. Upregulation of TRPCs, which form Ca²⁺-permeable non-selective cation channels, increases intracellular calcium, facilitating contraction, proliferation and migration. Induction of NHE1 results in an alkaline shift in intracellular pH and enhanced tethering of the actin cytoskeleton to the membrane via NHE1/ezrin interactions, which promote cell shape changes required for proliferation and migration.