EDHF and Gap Junctions: Important Regulators of Vascular Tone Within the Microcirculation

Abstract

Arterioles within the microcirculation control organ blood flow and represent the main peripheral resistance within the circulation. However, larger vessels with a diameter of more than 150 microm are mostly used to study vascular behavior. Although arterioles have features in common with these conducting vessels, they exhibit distinct properties and the contribution of different pathways to constriction or relaxation varies with vessel size. This is especially the case for endothelium-dependent relaxations, which occur in response to mechanical stimuli (e.g. blood flow) and agonists. Autacoids released from the endothelium include nitric oxide, prostaglandins and an endothelium-derived hyperpolarizing factor (EDHF). Whereas nitric oxide is dominant in larger vessels, the importance of EDHF increases with decreasing vessel size. Its chemical nature is still a matter of debate and different substances have been identified to act as an EDHF in different vascular beds, e.g. epoxyeicosanoids, potassium ions, anandamide, hydrogen peroxide or C-type natriuretic peptide. Despite this heterogeneity of proposed factors it is unclear if such a factor indeed exists in all vessels since the hyperpolarization of vascular smooth muscle has been proposed to be induced by simple current transfer from the adjacent endothelium. For this to occur the cells need to be electrically coupled and this requirement is fulfilled by gap junctions which are composed of connexins forming intercellular channels. Aside from myoendothelial coupling gap junctions also interconnect endothelial cells thus creating a functional unit, which efficiently synchronizes cellular behavior within the arteriolar tree of the microcirculation.

Junb regulates arterial contraction capacity, cellular contractility, and motility via its target Myl9 in mice

“…VSMCs are key effectors in the wall of blood vessels, determining their tone, resistance, and perfusion through their contractile capacity (1,31). As stress fiber formation provides a mechanism for both structural and biochemical adaptation of VSMCs to mechanical load (6), we mimicked the effect of pressure-induced deformation by subjecting cultured VSMCs to cyclic stretch followed by analysis of subsequent stress fiber formation.…”

“…Aberrant regulation of vascular tone plays an important role in the pathophysiology of major cardiovascular diseases including hypertension, myocardial infarction, and atherosclerosis (1)(2)(3). A primary determinant of vascular tone, hence resistance and regional blood flow, is the contractile capacity of VSMCs.…”

Diagnostic Biomarkers of Essential Arterial Hypertension The Value of Prostacyclin, Nitric Oxide, Oxidized-LDL, and Peroxide Measurements

“…18) Although arterioles have features in common with these conducting vessels, they exhibit distinct properties and the contribution of different pathways to constriction or relaxation varies with vessel size. This is especially the case for endothelium-dependent relaxations.…”

Reduced EDHF responses and connexin activity in mesenteric arteries from the insulin-resistant obese Zucker rat

“…Gap junctions are formed by the docking of two connexin subunits, each made up of six connexin proteins arranged around a central core [13], which creates a channel allowing the direct exchange of ions and lowmolecular-weight molecules [13]. Conduction studies have indicated that gap junctions between endothelial cells may be involved in the propagation of the EDHF response downstream along the vessel [14,15], and EDHF-attributed hyperpolarisations also propagate from endothelial cells through the entire smooth muscle layer via gap junctions, with a current that spreads with negligible attenuation [16].…”