Functional Role of Connexins and Pannexins in the Interaction Between Vascular and Nervous System

Abstract

The microvascular network of the microcirculation works in tight communication with surrounding tissues to control blood supply and exchange of solutes. In cerebral circulation, microvascular endothelial cells constitute a selective permeability barrier that controls the environment of parenchymal brain tissue, which is known as the blood-brain barrier (BBB). Connexin- and pannexin-formed channels (gap junctions and hemichannels) play a central role in the coordination of endothelial and smooth muscle cell function and connexin-mediated signaling in endothelial cells is essential in the regulation of BBB permeability. Likewise, gap junction communication between astrocyte end-feet also contributes to maintain the BBB integrity, but the participation of hemichannels in this process cannot be discarded. Sympathetic and sensory perivascular nerves are also involved in the control and coordination of vascular function through the release of vasoconstrictor or vasodilator signals and by the regulation of gap junction communication in the vessel wall. Conversely, ATP release through pannexin-1-formed channels mediates the α1-adrenergic signaling. Furthermore, here we show that capsaicin-induced CGRP release from mesenteric perivascular sensory nerves induces pannexin-1-formed channel opening, which in turn leads to reduction of pannexin-1 and endothelial nitric oxide synthase (eNOS) expression along the time. Interestingly, blockade of CGRP receptors with CGRP8-37 increased eNOS expression by ∼5-fold, suggesting that capsaicin-sensitive sensory nerves are involved in the control of key signaling proteins for vascular function. In this review, we discuss the importance of connexin-based channels in the control of BBB integrity and the functional interaction of vascular connexins and pannexins with the peripheral nervous system.

Contribution of Pannexin 1 and Connexin 43 Hemichannels to Extracellular Calcium–Dependent Transport Dynamics in Human Blood-Brain Barrier Endothelial Cells

“…Another possibility is that Px1 and Cx43 function in distinct localizations in brain capillary endothelial cells, e.g., Px1 on the luminal and/or abluminal membrane and Cx43 mainly in the gap junction regions. This is similar to the model proposed by Gaete et al (2014). In support of this notion, Px1 is localized on the plasma membrane of mouse inner retinal endothelial cells (Shestopalov and Panchin, 2008).…”

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

“…In life, there is evidence that the astrocyte endfeet are strongly linked to the basal side of the endothelial cells by numerous such integrin-dystroglycan complexes, involving integrins in the endothelial basal cell membrane interacting with extracellular laminin and fibronectin, connecting collagen IV and proteoglycans in the extracellular space to dystroglycan inserted in the underlying astrocyte end feet membrane. Similarly, it is proposed that the astrocytic layer forms an effective 'second barrier' surrounding the endothelial tube, with connexin 43 gap junctions linking adjacent astrocyte endfeet [64], and the whole complex being sufficiently tightly knit to restrict ready entry of leukocytes and mast cells to the brain parenchyma except in pathological conditions [57]. It is also possible that matrix components of the basal lamina (e.g., specific laminin composition [158]) may play a more important role than has been appreciated [74], e.g., in restricting the entry of cells into the parenchyma after their migration across brain endothelial cells or the transfer of very large macromolecules (e.g., ~ 460 kDa ferritin [20]) from the ECS to the perivascular space for clearance.…”

Role of connexins and pannexins in cardiovascular physiology

“…Clearly, more studies are needed before a consensus will be reached regarding involvement of Panx1 in alpha1-adrenergic receptor-mediated effects. It has also been suggested that release of calcitonin gene-related peptide (CGRP) from sensory-motor nerves can cause opening of Panx1 channels expressed by VSMCs in mouse mesenteric arteries [152]. However, as also noted by the authors, the physiological or pathophysiological relevance of CGRP-induced Panx1 channel opening remains to be determined [152].…”

“…It has also been suggested that release of calcitonin gene-related peptide (CGRP) from sensory-motor nerves can cause opening of Panx1 channels expressed by VSMCs in mouse mesenteric arteries [152]. However, as also noted by the authors, the physiological or pathophysiological relevance of CGRP-induced Panx1 channel opening remains to be determined [152]. Finally, Panx2 is expressed in the middle cerebral artery [153], but whether this or the expression of Panx3 in very small arteries has functional consequences is unknown.…”