Lack of vascular connexin 40 is associated with hypertension and irregular arteriolar vasomotion

Abstract

Gap-junctional communication coordinates the behavior of individual cells in arterioles. Gap junctions are formed by connexins 40 (Cx40), Cx43, Cx37, and Cx45 in the vasculature. Previously, we have shown that lack of Cx40 impairs conduction of dilatory signals along arterioles. Herein, we examined whether hypertension is present in conscious animals and whether this is a direct effect or due to secondary mechanisms. Mean arterial pressure was elevated by 20–25 mmHg in conscious Cx40-deficient mice (Cx40−/−) compared with wild-type controls in both sexes. Differences in heart rate were not observed. Blockade of NO synthase increased pressure equally in both genotypes. Conversely, the angiotensin AT1-receptor antagonist, candesartan, decreased pressure to similar extents in Cx40−/− and wild-type mice. Acetylcholine and sodium nitroprusside (0.05–15 nmol) were equally potent and effective in decreasing pressure and inducing dilatory responses in the microcirculation. However, in contrast to wild type, Cx40−/− arterioles exhibited spontaneous, irregular vasomotion leading temporarily to complete vessel closure. We conclude that loss of Cx40 is associated with hypertension independent of the action of angiotensin II. It is also not related to an altered efficacy of NO or other endothelial dilators. However, the observed irregular vasomotion suggests that peripheral vascular resistance is affected.

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

“…The physiological importance of connexin 40 has been identified in a number of studies reporting that a loss of connexin 40 (either through genetic mutation or connexin 40 inhibitors) results in an increase in blood pressure and a loss of vasocontrol [42,43]. The inhibition of gap junction communication with connexin-mimetic peptides 40 Gap27 or 43 Gap27 has been shown to block EDHF-mediated signal transmission in vivo, indicated by the abolition of NAME-and indomethacin-resistant renal vasodilation [43].…”

“…The results of studies conducted using connexin 40-deficient mice have also emphasised the importance of gap junctions, specifically, those associated with connexin 40, in the normal physiological transmission of endothelium-dependent vasodilation [44]. This set of studies showed that a lack of connexin 40 leads to the development of hypertension, and to irregular vasomotion in resistance arteries [42]. Another important outcome of these studies was the finding that the vessels needed to be locally stimulated with acetylcholine for the attenuated propagation along the endothelium to become apparent.…”

Connexin 40 Mediates the Tubuloglomerular Feedback Contribution to Renal Blood Flow Autoregulation

“…1,2 Genetic ablation of Cx40 causes severe impairment of conducted vasodilator responses in arterioles, 3,4 uncoordinated vasomotion, 5 and hypertension. [5][6][7] Furthermore, vascular expression of Cx40 is reduced in genetically hypertensive rats. 8 Within the kidney, gap junctions are prevalent in the juxtaglomerular apparatus (JGA).…”

Cerebrovascular Connexin Expression: Effects of Traumatic Brain Injury

“…Studies in knockout mice indicate that Cx40 has an important role in vascular development and blood pressure regulation (Figueroa and Duling, 2009). Ablation of Cx40 produced hypertension associated with irregular vasomotion, and interfered with the regenerative component of conducted vasodilation (de Wit et al, 2003). Thus increased expression of Cx40 protein in cerebral arteries 24 h after TBI may improve coordination of vasomotor tone and conduction of vasodilation signals, thereby contributing to restoration of vessel function, and thus may be a protective response to injury and a possible treatment target.…”