Vascular gap junctions and implications for hypertension

Abstract

SUMMARY1. Four connexin (Cx) molecules, namely Cx37, Cx40, Cx43 and Cx45, are expressed in the gap junctions that exist within and between the cellular layers of arteries.2. Endothelial cells are well coupled by large gap junctions expressing Cx37, Cx40 and, to a lesser extent, Cx43, whose expression may be more subject to regulation by physical factors.3. Smooth muscle cells are more heterogeneously coupled by gap junctions that are small and rare. The identity of the Cx expressed in the media may vary among different arteries.4. Myoendothelial gap junctions are small and more common in resistance arteries with fewer layers of smooth muscle cells. Given the small size of these gap junctions and the rapid turnover rate of Cxs, homocellular coupling in the media and heterocellular coupling between the cell layers may be subject to more dynamic control than coupling in the endothelium.5. Vascular gap junctions have been implicated in a number of vasomotor responses that may regulate vascular tone and blood pressure. These include the mechanism of action of the vasodilator, endothelium-derived hyperpolarizing factor (EDHF), the myogenic constriction to intramural pressure increase, the spontaneous or agonist-induced vasomotion of arteries and arterioles and the spreading vasodilation and constriction observed in microcirculatory networks.6. Few data are available on Cx expression in the media of resistance arteries during hypertension. Changes in the expression of Cx43 described in the media of the aorta of hypertensive rats vary with the hypertensive model studied and are likely to represent adaptations to structural changes in the vascular wall.7. In contrast, in the endothelium of the caudal and mesenteric arteries of spontaneously hypertensive rats, expression of Cxs is significantly decreased compared with arteries from normotensive rats and this decrease is reversed by inhibitors of the renin-angiotensin system. 8. During hypertension, the activity of EDHF is decreased in the mesenteric artery, but this occurs much later than the initial increase in blood pressure and the decrease in endothelial Cxs, suggesting that changes in EDHF may not be causally related to hypertension or to the changes in endothelial Cxs.9. Upregulation of the myogenic response and the incidence of vasomotion has been reported in hypertension. Little is currently known of the effects of hypertension on spreading vasomotor responses.10. Deletion of specific Cxs in genetically modified mice is complicated by neonatal lethality or coordinate regulation and compensatory changes in the remaining Cxs. Nevertheless, mice in which Cx40 has been deleted are hypertensive and spreading vasodilatory responses are significantly impaired.11. Determination of a role for specific Cxs in the control of blood pressure must await the development of animals in which Cx expression can be modulated in a more complex temporal and tissue-specific manner.

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

“…Perturbations in Cx production involving transcriptional and post-transcriptional mechanisms are increasingly recognised to accompany pathophysiological conditions such as ischaemic heart disease, heart failure, atrial fibrillation, hypertension and diabetes [1,2,13,14]. However, data using animals in which a specific Cx has been deleted suggest that compensatory changes may occur in the remaining Cxs [2].…”

“…However, data using animals in which a specific Cx has been deleted suggest that compensatory changes may occur in the remaining Cxs [2]. On the other hand, fine control of Cx structure through post-translational modifications such as phosphorylation may constitute additional mechanisms through which the function of gap junction could be disrupted.…”

“…Gap junctions comprising various connexins (Cxs) are abundantly produced throughout the cardiovascular system, providing direct electrical and chemical communication between adjacent cells to coordinate physiological responses such as cardiac rhythm and the regulation of vasomotor tone [1][2][3]. In the kidney, extensive coupling by gap junctions, involving Cx37 and Cx40, enables intercellular communication between the renin-secreting cells of the afferent arteriole, the endothelium and the mesangial cells, which, together with the macula densa, form the juxtaglomerular apparatus [4][5][6][7].…”

Correlation between connexin and traumatic brain injury in patients

“…Nevertheless, the development of strong correlation between CX40/CX43 levels of the tissue samples and GCS scores of TBI patients clearly point to the importance of CXs as critical players involved in brain injuries. In addition, metabolic conditions like diabetes and hypertension were indistinguishable between patient groups, minimizing potential confounding effects from other known factors on connexin expression (Figueroa, Isakson, & Duling, 2006; Hamelin, Allagnat, Haefliger, & Meda, 2009; Rummery & Hill, 2004; Wright, Richards, & Becker, 2012). …”

Endothelium-dependent relaxation is resistant to inhibition of nitric oxide synthesis, but sensitive to blockade of calcium-activated potassium channels in essential hypertension

“…9 On the basis of these data, these investigators suggest that a CYP2C9 product (11,12 epoxyeicosatrienoic acid (11,12 EET)) plays a key role in human EH as an endothelium-derived hyperpolarizing factor (EDHF) producing rapid compensatory vasorelaxation under conditions of decreased NO bioavailability. 9 The EDHF is a complex and multifaceted response, [10][11][12][13][14][15][16] playing a particularly prominent role in smaller resistance-sized vessels. 17 Evidence from eNOS-and cyclo-oxygenase-deficient mice is generally, 18,19 although not universally, 14 consistent with this proposed compensatory role for EDHFmediated arterial relaxation under conditions of NO deficiency.…”