Connexin 40-Mediated Regulation of Systemic Circulation and Arterial Blood Pressure

Abstract

Vascular system is a complex network in which different cell types and vascular segments must work in concert to regulate blood flow distribution and arterial blood pressure. Although paracrine/autocrine signaling is involved in the regulation of vasomotor tone, direct intercellular communication via gap junctions plays a central role in the control and coordination of vascular function in the microvascular network. Gap junctions are made up by connexin (Cx) proteins, and among the four Cxs expressed in the cardiovascular system (Cx37, Cx40, Cx43, and Cx45), Cx40 has emerged as a critical signaling pathway in the vessel wall. This Cx is predominantly found in the endothelium, but it is involved in the development of the cardiovascular system and in the coordination of endothelial and smooth muscle cell function along the length of the vessels. In addition, Cx40 participates in the control of vasomotor tone through the transmission of electrical signals from the endothelium to the underlying smooth muscle and in the regulation of arterial blood pressure by renin-angiotensin system in afferent arterioles. In this review, we discuss the participation of Cx40-formed channels in the development of cardiovascular system, control and coordination of vascular function, and regulation of arterial blood pressure.

What Is Next for Connexin and Pannexin?

“…The first connexin was not cloned until 1986 [7], but since then the field has rapidly expanded due to identification of 21 different human connexins with tissue-specific roles [8]. Of note, four connexin proteins (Cx): Cx37, Cx40, Cx43, and Cx45 are expressed and play a crucial functional role in blood vessels [2–4]. Gap junctions form when six-connexin oligomers, collectively known as a hemichannel or connexon, bind with another hemichannel on an adjacent cell to make a single nonselective pore that crosses both plasma membranes [9].…”

“…Cx40 expression varies throughout the vasculature and has been found in both ECs and SMCs, but it is thought to be predominately expressed in ECs, and much like Cx37, Cx40 is expressed between ECs and in myoendothelial junctions [4]. In the review by Márquez et al [4], the role of Cx40, in combination with other connexin proteins, in the development of the cardiovascular system is discussed.…”

“…Cx40 expression varies throughout the vasculature and has been found in both ECs and SMCs, but it is thought to be predominately expressed in ECs, and much like Cx37, Cx40 is expressed between ECs and in myoendothelial junctions [4]. In the review by Márquez et al [4], the role of Cx40, in combination with other connexin proteins, in the development of the cardiovascular system is discussed. Further, they explore the essential role for Cx40 in conducted vasodilation, a mechanism whereby electrotonic signals propagate between cells of the vascular wall, primarily through gap junctions, to ensure coordinated changes in diameter within a vascular network [17].…”

“…Thus, there are pathways including, but not limited to, the regulation of channel gating, transcription, and subcellular localization of connexins and pannexins that need to be further explored, in particular during pathology and physical stress, such as exercise. The reviews in this current volume [1–4] expand on these research areas and highlight the gaps in knowledge that need to be investigated before the targeting of connexins and pannexins can be fully translated from bench to bedside. There also remains technological challenges that need to be overcome to fully harness the therapeutic potential of connexins and pannexins.…”

“…Connexins and pannexins are among the most versatile transmembrane channel proteins, which shape cell behavior and tissue function with extraordinary finesse. In this volume, pannexins and connexins 37, 40, and 43 are reviewed [1–4], with special consideration for tissue specificity of expression, cell type-specific functions, and their roles in development and disease.…”