Spreading vasodilatation in the murine microcirculation: attenuation by oxidative stress-induced change in electromechanical coupling
Article first published online: 25 MAR 2013
© 2013 The Authors. The Journal of Physiology © 2013 The Physiological Society
The Journal of Physiology
Volume 591, Issue 8, pages 2157–2173, April 2013
How to Cite
Howitt, L., Chaston, D. J., Sandow, S. L., Matthaei, K. I., Edwards, F. R. and Hill, C. E. (2013), Spreading vasodilatation in the murine microcirculation: attenuation by oxidative stress-induced change in electromechanical coupling. The Journal of Physiology, 591: 2157–2173. doi: 10.1113/jphysiol.2013.250928
- Issue published online: 15 APR 2013
- Article first published online: 25 MAR 2013
- Accepted manuscript online: 5 MAR 2013 07:36AM EST
- (Received 2 January 2013; accepted after revision 19 February 2013; first published online 25 February 2013)
- • Regulation of blood flow in microcirculatory networks depends on spread of local vasodilatation to upstream supply arteries.
- • This is mediated by endothelial conduction of hyperpolarization, attenuation of which is expected to occur through current restriction or loss at sites of cell coupling and open ion channels in cell membranes.
- • In an animal model of hypertension, we found that hyperpolarization decays more rapidly when endothelial cell coupling is reduced; however, this could not fully explain the observed attenuation in conducted vasodilatation.
- • We found that increased oxidative stress, due to upregulation of angiotensin II, changed the contribution of L- and T-type calcium channels to resting vessel tone. Inhibition of oxidative stress reversed this change and improved conducted vasodilatation.
- • Our data suggest that cardiovascular disease may impair the ability of microvascular networks to maintain tissue integrity, due to oxidative stress-induced changes in the way blood vessels constrict.
Abstract Regulation of blood flow in microcirculatory networks depends on spread of local vasodilatation to encompass upstream arteries; a process mediated by endothelial conduction of hyperpolarization. Given that endothelial coupling is reduced in hypertension, we used hypertensive Cx40ko mice, in which endothelial coupling is attenuated, to investigate the contribution of the renin–angiotensin system and reduced endothelial cell coupling to conducted vasodilatation of cremaster arterioles in vivo. When the endothelium was disrupted by light dye treatment, conducted vasodilatation, following ionophoresis of acetylcholine, was abolished beyond the site of endothelial damage. In the absence of Cx40, sparse immunohistochemical staining was found for Cx37 in the endothelium, and endothelial, myoendothelial and smooth muscle gap junctions were identified by electron microscopy. Hyperpolarization decayed more rapidly in arterioles from Cx40ko than wild-type mice. This was accompanied by a shift in the threshold potential defining the linear relationship between voltage and diameter, increased T-type calcium channel expression and increased contribution of T-type (3 μmol l−1 NNC 55-0396), relative to L-type (1 μmol l−1 nifedipine), channels to vascular tone. The change in electromechanical coupling was reversed by inhibition of the renin–angiotensin system (candesartan, 1.0 mg kg−1 day−1 for 2 weeks) or by acute treatment with the superoxide scavenger tempol (1 mmol l−1). Candesartan and tempol treatments also significantly improved conducted vasodilatation. We conclude that conducted vasodilatation in Cx40ko mice requires the endothelium, and attenuation results from both a reduction in endothelial coupling and an angiotensin II-induced increase in oxidative stress. We suggest that during cardiovascular disease, the ability of microvascular networks to maintain tissue integrity may be compromised due to oxidative stress-induced changes in electromechanical coupling.