Abstract
Connexins (Cxs) are gap junction forming transmembrane proteins and play a pivotal role in maintaining vascular tone. Recent evidence suggests their sister proteins the Pannexins may also be involved. Alterations in connexin mediated signalling are proposed to play a role in abnormal vasoconstriction processes.The first part of this study was conducted on rat mesenteric arteries and verified that nitric oxide contributes to regulation of vascular tone. A derivative of the connexin mimetic peptide Gap27 (Compound A), Carbenoxolone, the Pannexinl antagonist glibenclamide and the purinergic receptor antagonist suramin attenuated contraction of mesenteric vessels pre-constricted with the thromboxane A2 agonist (U46619) but not with endothelin-1 (ET-1), suggesting a role for connexin or Pannexin mediated signalling. The later parts of the study were performed in mouse pulmonary vasculature and showed that NO-dependent vasodilation required Cx43. Reduced Cx43 signalling was associated with impaired pulmonary vasodilatory responses in both male and female mice. Gap27 also attenuated isoprenaline-induced relaxation in intra-lobar pulmonary arteries(IPAs) which have a small NO component. In addition, altered contractile responses to ET-1 in IPAs under both normoxic and hypoxic conditions in male Cx43 heterozygous (Cx43+/') mice were observed. Serotonin (5-HT)mediated contraction in IPAs was not altered by reduction of Cx43. By contrast, contractile responses to 5-HT, but not ET-1, were altered in mouse thoracic aortas. Vasodilatory responses to the slowly hydrolysable ACh analogue methacholine (MCh) were not altered in the thoracic aortas ofCx43+/" mice. A gender difference in connexin expression in pulmonary arteries (main and branch) where female mice had higher Cx43 levels than male mice was observed in both WT and Cx43+/" mice. Among the male and female Cx43+/~ mice, compensatory changes such as downregulation ofCx37, Cx40, Cx45 and Pannexinl were observed only in the males. Chronichypoxia suppressed Cx43 expression in both male wild type (WT) andCx43+/' mice.
In conclusion, reduced Cx43 signalling is associated with pulmonary vascular dysfunction in mice. There is a gender difference in connexin gene expression in mouse pulmonary vasculature.
| Date of Award | 2018 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Jane Nally (Supervisor), Yvonne Dempsie (Supervisor) & Patricia Martin (Supervisor) |