Endothelial mediators and communication through vascular gap junctions

Abstract

Cellular interaction in vessels is achieved by multiple communication pathways, including gap junctions (GJs). They provide intercellular channels, allowing direct interaction of endothelial and smooth muscle cells and the coordination of cellular behaviour along the vessel. The latter is a prerequisite for large flow increases because an adaptation of resistance along the vessel length is required. Longitudinal communication is studied by confined local stimulation of arterioles and the observation of responses at distant locations. Certain vascular stimuli induce local and concomitant remote responses of a similar type, verifying rapid longitudinal conduction of vasomotor signals, most likely changes in membrane potential. This is achieved for dilatory responses via the endothelium, possibly by an endothelium-derived hyperpolarising factor (EDHF) that induces local hyperpolarisation, which is then transferred to remote sites through GJs. In vessels, GJs are composed of different connexins (Cx), but Cx40 is of special importance because its lack impairs longitudinal conduction of vasodilations. Interestingly, Cx40-deficient mice are hypertensive, suggesting that Cx40-dependent coupling is necessary to regulate vascular behaviour and peripheral resistance. While the role of other connexins is less well established, an abundance of data has proven the necessity of GJ communication to coordinate vascular behaviour during blood flow regulation.

Loss of connexin40 is associated with decreased endothelium-dependent relaxations and eNOS levels in the mouse aorta

“…In response to agonist stimulation of endothelial cells, a subsequent relaxation of smooth muscle cells occurs. Indeed agonists such as ACh or ATP can stimulate the production of endothelium-derived vasodilators such as nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarizing factor (EDHF) depending on the vascular bed (10,15,17,42).…”

“…Endothelial cells are connected by gap junctions, allowing the exchange of ions, second messengers, or metabolites and the spreading of hyperpolarization between adjacent cells (10,13,15,23).…”

“…Gap junction channels connecting the cytosol of adjacent endothelial cells are composed of two connexons formed by six connexin proteins, and the association of two connexons in the plasma membrane of adjacent cells provides a functional gap junction channel that enables cell-to-cell communication (10,15,22). Among the 20 different connexin types, four are expressed in the cardiovascular system (Cx40, Cx37, Cx43, and Cx45), but their expression shows significant variations in different vascular beds or species (10,15,22,41).…”

“…Among the 20 different connexin types, four are expressed in the cardiovascular system (Cx40, Cx37, Cx43, and Cx45), but their expression shows significant variations in different vascular beds or species (10,15,22,41). In endothelial cells of mice, Cx40 and Cx37 are predominantly expressed, although the expression of Cx43 has also been reported in a few cases (22,26,33,35,39).…”

Endogenous and exogenous NO attenuates conduction of vasoconstrictions along arterioles in the microcirculation

“…There is good experimental evidence to support this idea, because hyper-or depolarizations originating at discrete sites after focal stimulation can be demonstrated at remote sites in vascular cells along the vessel length (11,32,39). Because gap junctions form intercellular low-resistance channels, they allow the spread of electrotonic signals longitudinally along the vessel through a layer of coupled cells (7).…”