Connexin-mediated regulation of the pulmonary vasculature

Abstract

Pulmonary arterial hypertension (PAH) is a complex, multi-factorial disorder characterized by both constriction and remodelling of the distal pulmonary vasculature. This leads to increased pulmonary pressures and eventually right heart failure. Current drugs, which primarily target the vasoconstriction, serve only to prolong life and novel therapies targeting both the vasoconstriction and the remodelling are required. Aberrant signalling between cells of the pulmonary vasculature has been associated with the development of PAH. In particular, endothelial dysfunction can lead to hyperplasia of the underlying medial layer. Connexins are a family of transmembrane proteins which can form intercellular communication channels known as gap junctions. This review will discuss recent evidence which shows that connexins play a role in regulation of the pulmonary vasculature and that dysregulation of connexins may contribute to PAH pathogenesis. Interaction of connexins with signalling pathways relevant to the pathogenesis of PAH, such as bone morphogenetic protein (BMP), serotonin and oestrogen are discussed.

Connexin 43 Plays a Role in Pulmonary Vascular Reactivity in Mice

“…PAH is far more common in females than in males (~3:1) [ 3 ]. Dysregulation of cell-to-cell communication particularly between pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) is thought to play an important role in both constriction and remodeling of the pulmonary vasculature in PAH [ 4 ]. For example, PAECs from patients with PAH have increased gene and protein expression of tryptophan hydroxylase 1 (Tph1), which is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT) [ 5 ].…”

Evaluation of endothelial nitric oxide synthase gene expression in mice genetically heterozygous in Cx43 (Cx43 + / - mice)

“…From the heart, the pulmonary arteries supply deoxygenated blood to the lungs where gas exchange takes place within the pulmonary capillaries [5]. PAH is a multifactorial disease characterized by constriction and remodelling of the pulmonary vasculature, which is the basis for the persistently high pulmonary pressures [6]. The process of vascular remodelling gives rise to increased and disorganised proliferation of smooth muscle cells (SMCs), pulmonary endothelial cells and fibroblasts, thus resulting in reduction in the number of distal arterial vessels as a consequent of increased muscularization of the arteries, which later progresses and leads to vessel occlusion and then finally, formation of plexiform lesion.…”

“…The exact pathogenesis of PAH is not completely understood, however, serotonin, bone morphogenetic protein receptor type 2 and NO pathways have been shown to play major roles in the development of the disease [13,14]. There is need for novel drugs therapies targeting both vasoconstriction and remodelling, which can only be achieved with known pathogenesis [6]. PAH, which represents group one within the pulmonary hypertension WHO clinical classification system can be further classified, based on aetiology, into idiopathic PAH (IPAH), heritable PAH (HPAH), drug and toxin-induced PAH, associated PAH (APAH) and Persistent pulmonary hypertension of the new born (PPHN) [15].…”

“…Cell -cell communication via gap junctions is essential in controlling normal vascular function [22,23]. These cellular communications involve a family of transmembrane proteins called connexins which oligomerize into a hemichannel and eventually pair with a partner hemichannel in an adjacent cell forming gap junctions that allow cell-to-cell coupling between endothelial and SMC [6,24]. Key connexin family members involved in the vasculature include connexin 37 (Cx37), connexin 40 (Cx40), connexin 43 (Cx43) and connexin 45 (Cx45), and all play significant role in regulation of vascular function such as mediation of vascular tone, vascular growth, angiogenesis, cell development and differentiation [25] and the passage of cGMP and Ca 2+ , thus regulating vascular tone [26].…”

“…eNOS gene expression levels were found to be the same in all four groups of mice tested, with no significant difference. The result therefore suggests that eNOS gene is expressed in mice genetically heterozygous in Cx43 (Cx43 + / -).Recent data reveal that in PAH patients, the mean resting pulmonary artery pressure rises above 25 mmHg [6] and tends to increase further to 30 mmHg during exercise [8]. Elevated arterial blood pressure is a key risk factor leading to cardiovascular diseases such as right heart failure which is the main cause of mortality In PAH patients [9,10].…”