Dora Group | Vascular Pharmacology Research

+44 (0)1865 281114
kim.dora@pharm.ox.ac.uk

Studying coronary tissue from patients has added an extra dimension to our work

Closely linked to the Vascular Pharmacology Research Group with Prof Chris Garland

We use electrophysiological and live cell imaging techniques to investigate the fundamental mechanisms controlling the diameter of small arteries and arterioles in health and disease.

Cell-cell contacts in a human coronary arteriole, diameter 120µm, imaged with SEM.

We study the resistance arteries and arterioles within tissue that hold blood pressure and regulate tissue blood flow. Hyperpolarizing current can pass through the arteriolar wall and signal local and conducted dilation. This process occurs with every heart beat, when we move and when we think. The endothelium is crucial for this response, acting as a conduit for the movement of current. Therefore any disease that damages the endothelium, or any drug that prevents hyperpolarization could have deleterious consequences on tissue perfusion.

Our aim is to unravel this complex intra and intercellular signalling in arterioles, to define how vasoconstriction and vasodilation is regulated and to identify what goes wrong in cardiovascular disease, which remains the most prevalent cause of morbidity and mortality in the adult population.

To do this, we study isolated microvessels maintained under physiological conditions of pressure and intraluminal flow, including human coronary arterioles, using electrophysiology, advanced live cell imaging, and pharmacological tools.

We have defined how endothelial cells elaborate hyperpolarization or EDH, which they use to affect vasodilatation, and show it passes to the smooth muscle layers by way of myoendothelial gap junctions and the extracellular accumulation of potassium ion (Nature 396, 269-272; Acta Physiol. 219, 202-218). We then discovered that projections of endothelial cells (MEPs) to the smooth muscle contain signalling complexes including IK_Ca channels (J Physiol., 553, 183-189; Circ. Res. 97, 399-407; Circ. Res. 102, 1247-1255), and that by generating EDH these complexes can link low arterial pressure to the modulation of myogenic tone (Proc. Nat. Acad. Sci. USA 109 (44), 18174-9) and most recently that when sympathetic stimulation is high attenuate vasoconstriction and activate the physiologically important response of vasomotion, that optimizes tissue blood flow.