Fibroblasts in Pulmonary Hypertension: Roles and Molecular Mechanisms

Abstract

Fibroblasts, among the most prevalent and widely distributed cell types in the human body, play a crucial role in defining tissue structure. They do this by depositing and remodeling extracellular matrixes and organizing functional tissue networks, which are essential for tissue homeostasis and various human diseases. Pulmonary hypertension (PH) is a devastating syndrome with high mortality, characterized by remodeling of the pulmonary vasculature and significant cellular and structural changes within the intima, media, and adventitia layers. Most research on PH has focused on alterations in the intima (endothelial cells) and media (smooth muscle cells). However, research over the past decade has provided strong evidence of the critical role played by pulmonary artery adventitial fibroblasts in PH. These fibroblasts exhibit the earliest, most dramatic, and most sustained proliferative, apoptosis-resistant, and inflammatory responses to vascular stress. This review examines the aberrant phenotypes of PH fibroblasts and their role in the pathogenesis of PH, discusses potential molecular signaling pathways underlying these activated phenotypes, and highlights areas of research that merit further study to identify promising targets for the prevention and treatment of PH.

Keywords: adventitial fibroblast; epigenetics; gene regulation; hypoxia; inflammation; metabolism; mitochondrial; pulmonary arterial hypertension; vascular remodeling.

Figure 1

Persistently activated pulmonary artery adventitial fibroblasts regulate the phenotype of adventitial immune cells (macrophage and T-cells) in PH. (A) Naïve bone-marrow-derived macrophages (BMDMs) were treated with media conditioned with pulmonary artery adventitial fibroblasts isolated from hypoxia-induced pulmonary hypertensive (PH-CM) or age-matched control calves (CO-CM) or left untreated (UNX). Genes from RNA-seq that are uniquely regulated by CO-CM or PH-CM were analyzed by Ingenuity Pathway Analysis (IPA). The significantly regulated canonical pathways of BMDMs by these genes demonstrated that the CO-CM (left) and PH-CM (right) have very different effects on regulating BMDM phenotypes. The pathways were selected with p ≤ 0.05 and absolute Z ≥ 2. The size of the bubble indicates the number of genes in that pathway. (B) IPA predicted upstream regulators in CO-CM- (left) and PH-CM-treated (right) BMDMs (p ≤ 0.05, absolute Z ≥ 2). The upstream regulators are transcripts, proteins, or metabolites that are predicted based on the downstream targets identified by RNA-seq. (A,B) here were modified from our own publication (Figure 1, Front Immunol 2021 Mar 31:12:640718, reference [86]) (C) The complicated microenvironment of the PH pulmonary artery adventitial area regulates the phenotype and function of adventitial macrophages and T-cells.

Figure 2

Schematic presentation of mechanisms showing how the HDAC–miR-124–PTBP1/PKM axis controls metabolic reprogramming and the subsequent regulation of phenotypes by the sensor and regulator of glycolysis CtBP1 in PH-Fibs.

Figure 3

Hypothetical representation of chromatin structure, transcription factors (TFs), and TF co-regulators in normal (top panel) and persistently “activated” PH vascular cells (lower panel) of genes involved in proliferation, apoptosis resistance, and proinflammation. We posit that the persistently high expression of these genes in PH vascular cells is due to their “open” chromatin structure, allowing the binding of multiple stress-related TFs and pioneer TF(s), which helps maintain an active chromatin structure and high levels of gene expression by recruiting and maintaining high levels of TF co-factors including epigenetic regulators such as HATs, BRDs, and the Mediator Complex (lower panel). Abbreviations: Ac, acetylation; EGR1, early growth response 1; p-TEFb, positive transcription elongation factor B; Pol II, RNA polymerase II.