Endothelial connexins in vascular function

Abstract

Gap junctions are essential for intercellular crosstalk in blood and lymphatic vasculature. These clusters of intercellular channels ensure direct communication among endothelial cells and between endothelial and smooth muscle cells, and the synchronization of their behavior along the vascular tree. Gap junction channels are formed by connexins; six connexins form a connexon or hemichannel and the docking of two connexons result in a full gap junction channel allowing for the exchange of ions and small metabolites between neighboring cells. Recent evidence indicates that the intracellular domains of connexins may also function as an interaction platform (interactome) for other proteins, thereby regulating their function. Interestingly, fragments of Cx proteins generated by alternative internal translation were recently described, although their functions in the vascular wall remain to be uncovered. Variations in connexin expression are observed along different types of blood and lymphatic vessels; the most commonly found endothelial connexins are Cx37, Cx40, Cx43 and Cx47. Physiological studies on connexin-knockout mice demonstrated the essential roles of these channel-forming proteins in the coordination of vasomotor activity, endothelial permeability and inflammation, angiogenesis and in the maintenance of fluid balance in the body.

HiPS-Endothelial Cells Acquire Cardiac Endothelial Phenotype in Co-culture With hiPS-Cardiomyocytes

“…Moreover, upregulation of several angiogenic genes were detected in hiPS-CMs and their receptors in hiPS-ECs, reflecting enhanced angiogenic signaling from CM to EC via cardiokines (e.g., VEGFA and VEGFB). Interestingly, several junctional protein genes were upregulated in hiPS-ECs in co-culture, potentially indicating that the presence of hiPS-CMs led to improved endothelial barrier function, cellular crosstalk and stability (Komarova et al, 2017;Hautefort et al, 2019). We also observed a similar effect in flow-exposed hiPS-ECs (Helle et al, 2020).…”

“…The expression of several junctional protein genes and their regulators were increased in hiPS-ECs in co-culture (Supplementary Table 1 and Supplementary Figure 4C). These included genes coding for adherens junction related proteins [CDH5 (VE-cadherin), Catenin alpha-1 (CTNNA1) Catenin beta-1 (CTNNB1), and the tyrosine phosphatase VE-PTP (PTPRB) Harris and Tepass, 2010;Nawroth et al, 2002)], tight junction related proteins [ESAM1 (Nasdala et al, 2002) and CLDND1 (Mineta et al, 2011)], and gap junction proteins Cx40 (GJA5) and Cx45 (GJC1) (Hautefort et al, 2019). In addition, the expression TIE1 and TEK (TIE2), which have important roles in angiogenesis, vascular remodeling and endothelial barrier function (Savant et al, 2015;Komarova et al, 2017) were induced in co-culture hiPS-ECs.…”

Neurovascular Coupling in Development and Disease: Focus on Astrocytes

“…Endothelial cells are interconnected via gap junctions, which allows them to propagate vasoactive signals from the nearby neuropil or vascular mural cells to adjacent endothelial cells, leading to conducted contractility changes. This allows local vascular networks to respond to mechanical or chemical stimuli as one unit ( Hautefort et al, 2019 ). Endothelial cells may also play an active role in NVC ( Hogan-Cann et al, 2019 ) by sensing signals from astrocytes and neurons and then releasing dilators like NO onto contractile vascular mural cells ( Stobart et al, 2013 ; Zuccolo et al, 2017 ).…”

“…Pericytes are functionally coupled to endothelial cells via gap junctions in both rodents and humans ( Cuevas et al, 1984 ; Kovacs-Oller et al, 2020 ). Endothelial cells are tightly coupled together by gap junctions ( Hautefort et al, 2019 ) to allow electrotonic conduction along the vasculature ( Segal and Duling, 1986 ; Welsh and Segal, 1998 ; Emerson and Segal, 2000 ). This relationship permits locally sensed contractile signals in one pericyte to be conducted along the endothelium and conveyed to distant pericytes ( Wu et al, 2006 ) or upstream arterioles ( Longden et al, 2017 ).…”

Mechanisms of Mechanical Force Induced Pulmonary Vascular Endothelial Hyperpermeability

“…In ECs, GJs play an important role in regulating the permeability of the endothelial monolayer. Cx37, Cx40, and Cx43 are abundantly expressed in different lung ECs and involved in endothelial permeability ( Nagasawa et al, 2006 ; Hautefort et al, 2019 ). Cx37 functions as a break of ECs proliferation and overexpression of Cx37 facilitates ECs apoptosis, indicating that Cx37 plays a crucial role in angiogenesis and vascular repair ( Seul et al, 2004 ; Pohl, 2020 ).…”