Vascular Gap Junctions in Hypertension

Figueroa, Xavier F.; Isakson, Brant E.; Duling, Brian R.

doi:10.1161/01.hyp.0000242483.03361.da

Cited by 56 publications

(72 citation statements)

References 126 publications

(112 reference statements)

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“…[1][2][3]9,10 Second, we focused on the relationship between Cxs and eNOS, 5,8,15 a key EC enzyme for the production of NO, which relaxes SMCs, thus contributing to the control of blood pressure. 5,14,22,25 We now show that volume-dependent hypertension promotes the interaction of Cx40 and Cx37 with eNOS and that this interaction results in increased release of NO. Our data suggest that this interaction starts during the cytosolic trafficking of connexins, raising the possibility that it may be facilitated with partially oligomerized Cxs or individual connexons.…”

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confidence: 61%

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Interplay Between Connexin40 and Nitric Oxide Signaling During Hypertension

et al. 2015

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A fter a chronic increase in blood pressure, arteries undergo alterations of endothelial (ECs) and smooth muscle cells (SMCs) because of hemodynamic changes.1 Specifically, hypertension results in the hypertrophic remodeling of arterial walls, 2,3 which associates with altered expression of connexins (Cxs). [4][5][6][7][8] These proteins form channels for the communication of ECs and SMCs, which is needed to coordinate vasoconstriction and vasodilation along the vessels.9 ECs predominantly express Cx37 and Cx40, [5][6][7] whereas SMCs mostly express Cx43 and Cx45. 5,6,10 Mice lacking Cx40 feature hypertension 4,6,11,12 because of increased secretion of renin 4,13 and reduced relaxation of peripheral vessels.14 This effect may be the link to the decreased expression of endothelial nitric oxide synthase (eNOS), 5,15 which impairs the release of NO, whereby ECs usually relax SMCs. [4][5][6]13 Thus, restoration of Cx40 in ECs of Cx40−/− mice normalizes eNOS levels, 8 suggesting an interaction between these proteins. As yet, however, such interaction has not been tested during hypertension.To investigate this question, we have subjected wild-type (WT) and Cx40-null mice (Cx40−/−) 4,13 to conditions inducing hypertension by either volume overload (after a 1-kidney, 1-clip [1K1C] procedure 16,17 ) or renin overproduction (after a 2-kidney, 1-clip [2K1C] procedure 6 ). We show that Cx40 consistently increased in aortic ECs, whereas Cx37 and Cx45 increased in SMCs, irrespective of the mechanism leading to hypertension. In contrast, Cx43 only increased in SMCs during renin-dependent hypertension. The volume-dependent hypertension of WT mice was associated with an increased interaction between Cx40 and Cx37 with eNOS, whereas Cx40−/− null mice featured decreased levels of eNOS and increased phosphorylation of the enzyme. The results provide evidence that Cx40 and Cx37 of ECs activate different signaling mechanisms depending on the cause of hypertension. MethodsSee online-only Data Supplement. Results 1K1C Procedure Induces Volume-Dependent HypertensionCompared with untreated WT controls, WT 1K1C mice featured increased blood pressure, heart weight, kidney index, and thickeness of the aortic media (Tables S2 and S3 in the online-only Data Supplement). These alterations occurred in Abstract-Connexins (Cxs) and endothelial nitric oxide synthase (eNOS) contribute to the adaptation of endothelial and smooth muscle cells to hemodynamic changes. To decipher the in vivo interplay between these proteins, we studied Cx40-null mice, a model of renin-dependent hypertension which displays an altered endothelium-dependent relaxation of the aorta because of reduced eNOS levels. These mice, which were either untreated or subjected to the 1-kidney, 1-clip (1K1C) procedure, a model of volume-dependent hypertension, were compared with control mice submitted to either the 1K1C or the 2-kidney, 1-clip (2K1C) procedure, a model of renin-dependent hypertension. All operated mice became hypertensive and featured hypertrophy and altered Cx express...

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confidence: 61%

“…6,20,21 Still, it is not clear whether vascular Cx are similarly changed in all forms of hypertension, 22 and, if so, how these changes affect blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Interplay Between Connexin40 and Nitric Oxide Signaling During Hypertension

et al. 2015

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“…1). The expression of connexins has been reported to be altered in several animals models of pathologies associated with vascular complications (15), such as hypertension (56,159) and diabetes (95,215), which highlights the importance of the direct cell-to-cell interaction for vascular homeostasis.…”

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confidence: 99%

“…Rather, the connexins mediate specific cell-to-cell signaling pathways, and the molecular selectivity as well as subcellular localization differs among connexin (55,56,129,162,203). Thus, although these proteins may have some overlap in function, they work in concert (55,56,79,182,183) and, in many cases, the function of one connexin cannot be replaced by other connexin isoform (79,203,206,216). In addition, hemichannels can be composed of one (homomeric channels) or a mixture (heteromeric channels) of connexin proteins.…”

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confidence: 99%

Gap Junctions in the Control of Vascular Function

Figueroa

Duling

2009

Antioxidants & Redox Signaling

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248

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Direct intercellular communication via gap junctions is critical in the control and coordination of vascular function. In the cardiovascular system, gap junctions are made up of one or more of four connexin proteins: Cx37, Cx40, Cx43, and Cx45. The expression of more than one gap-junction protein in the vasculature is not redundant. Rather, vascular connexins work in concert, first during the development of the cardiovascular system, and then in integrating smooth muscle and endothelial cell function, and in coordinating cell function along the length of the vessel wall. In addition, connexin-based channels have emerged as an important signaling pathway in the astrocyte-mediated neurovascular coupling. Direct electrical communication between endothelial cells and vascular smooth muscle cells via gap junctions is thought to play a relevant role in the control of vasomotor tone, providing the signaling pathway known as endothelium-derived hyperpolarizing factor (EDHF). Consistent with the importance of gap junctions in the regulation of vasomotor tone and arterial blood pressure, the expression of connexins is altered in diseases associated with vascular complications. In this review, we discuss the participation of connexin-based channels in the control of vascular function in physiologic and pathologic conditions, with a special emphasis on hypertension and diabetes. Antioxid. Redox Signal. 11, 251-266. 251

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“…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). …”

Section: Discussionmentioning

confidence: 99%

Correlation between connexin and traumatic brain injury in patients

Chen

Sun

et al. 2017

Brain and Behavior

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BackgroundIdentification of molecular alterations of damaged tissue in patients with neurological disorders can provide novel insight and potential therapeutic target for treatment of the diseases. It has been suggested by animal studies that connexins (CXs), a family of gap junction proteins, could contribute to neuronal cell death and associate with neurological deficits during trauma‐induced damage. Nevertheless, whether specific CXs are involved in traumatic brain injury (TBI) has remained unexplored in human patients.MethodsIn a clinical setting, we performed a correlation study of 131 TBI patients who received brain surgery. CXs (including CX40, CX43, and CX45) were examined in the harvested brain tissues for studying the relationships with the Glasgow Coma Scale scores of the patients.ResultsSpecifically, the protein levels of CX43 (negatively) and CX40 (positively) are associated with the extent of disease severity. Meanwhile, the phosphorylation status of CX43 was strongly associated with the severe TBI patients who contain relatively high kinase activities of PKC (protein kinase C) and MAPK (mitogen‐activated protein kinase), two possible activators for CX43 phosphorylation.ConclusionThese data highlight that a cluster of connexin family gap junction proteins not previously studied in humans is significantly correlated with the disease progression of TBI.

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Vascular Gap Junctions in Hypertension

Cited by 56 publications

References 126 publications

Interplay Between Connexin40 and Nitric Oxide Signaling During Hypertension

Interplay Between Connexin40 and Nitric Oxide Signaling During Hypertension

Gap Junctions in the Control of Vascular Function

Correlation between connexin and traumatic brain injury in patients

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