The potential role of TRPV1 in pulmonary hypertension: Angel or demon?

Abstract

Pulmonary hypertension (PH) is a pathological state defined by increased pulmonary artery pressure, the pathogenesis of which is related to genetic mutations, intracellular calcium ([Ca 2+ ] i), inflammation and proliferation. Transient receptor potential vanilloid subfamily member 1 (TRPV1) is a nonselective cation channel expressed in neural and nonneural cells, including pulmonary vessels and nerves. As a calcium channel, TRPV1 can make vessels contracted, and promote smooth muscle cells proliferation through calcium-dependent transcription factors. Activation of TRPV1 in sensory nerves can release neuropeptides, including calcitonin generelated peptide (CGRP), substance P (SP), and somatostatin (SST), which can regulate inflammation via transcription factor NF-kB. Considering the increased level of [Ca 2+ ] i and inflammation in the pathogenesis of PH, our review summarizes the role of TRPV1 in PH with regard to [Ca 2+ ] i , neuropeptides, and inflammation. In view of the limited research illustrating the relationship between TRPV1 and PH directly, our review also considers the role of TRPV1 in other types of vascular inflammation. Through this review, we hope to raise awareness about the function of TRPV1 in PH.

TRPC and TRPV Channels’ Role in Vascular Remodeling and Disease

“…Studies with animal models of common vascular diseases, like systemic and pulmonary hypertension, atherosclerosis and restenosis, which use KO mice of different TRP isoforms, suggest the translational potential role of TRPC and TRPV channels. Previous cutting-edge studies have suggested that these channels might be major regulators of cellular remodeling through their ability to modulate transcriptional programs that drive cell proliferation and migration, and even cytokine secretion [ 18 , 70 , 92 ]. As reviewed above, there is general agreement that most isoforms of TRPCs are implicated in cellular remodeling, a critical step for vascular disease progression, which occurs in systemic and pulmonary hypertension, atherosclerosis and restenosis.…”

“…Meanwhile, TRPV1, V3 or V4 likely play a protective role in systemic hypertension and atherosclerosis, since they participate in NO release via endothelium and metabolism lipid regulation [ 87 , 101 , 108 , 109 ]. In contrast, TRPV1 and V4 activation seem critical for hypoxia-induced Ca 2+ increase and further PASMCs proliferation and migration [ 92 , 117 ]. Nevertheless, future studies are urgently needed to address the downstream targets and mechanisms modulated by these channels, as well as the upstream regulators leading to changes in their expression and function during disease.…”

“…Upregulation of TRPV1, V3 and V4 in the PASMCs of patients with idiopathic PAH [89][90][91]. TRPV1 and TRPV4 activation evokes Ca 2+ influx, proliferation and contraction of PASMCs [85,89,90,92]. TRPV4 plays a role in fibroblast proliferation and the synthesis of the extracellular matrix in lungs [93].…”

“…TRPVs: Independent studies suggested that TRPV1, V3 and V4 also play a role in PASMCs’ proliferation and PAH. TRPV1 activation increased [Ca 2+ ] i in PASMCs, which enhanced vascular contraction, proliferation and migration through NFAT and CREB activation [ 92 ]. The incubation of PASMCs with hypoxia activated TRPV1 and V4, which increased PASMCs’ migration and cytoskeleton reorganization [ 117 ].…”

Cannabinoids—A New Perspective in Adjuvant Therapy for Pulmonary Hypertension

“…Zhang et al [ 71 ] suggested that, on the one hand, TRPV1 induces an increase in intracellular calcium ([Ca 2+ ] i ) in PASMCs and can cause vascular contractions, as well as promoting smooth muscle cell proliferation, which can lead to PH. On the other hand, the activation of TRPV1 in sensory nerves can release neuropeptides, including the calcitonin-gene-related peptide (CGRP) [ 71 ]. CGRP causes the relaxation of blood vessels and inhibits their proliferation, which may be beneficial in PH [ 71 ].…”