Garland Group | Vascular Pharmacology Research

We were responsible for discovering which potassium (K) channels generated endothelium-dependent hyperpolarization (EDH; both IKCa and SKCa channels) and showing EDH is the predominant endothelial vasodilator pathway in the microcirculation and how it passes to the adjacent smooth muscle to affect vasodilatation. Following these discoveries we suggested the presence of endothelial cell signalling microdomains and have found endothelial cell projections to the smooth muscle represent a key signalling complex, particularly involving the activation of IKCa channels to regulate arteriolar vasomotion and with TRPV4 channels myogenic tone.

We study the very small resistance arteries and arterioles responsible for directing blood to and within the tissues and organs of the body, to provide oxygen and nutrients. These microvessels also present the major component of the peripheral resistance to blood flow, and as a result they regulate blood pressure in the body as well. Their critical physiological role is mediated by tightly controlled communication or signalling between the endothelial, smooth muscle and nerve cells that form blood vessels.

Our aim is to unravel this complex intra and intercellular signalling in small arteries/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. doi:10.1111/apha.12649).  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; Science Signaling, 7 (333) pe 16) and most recently that when sympathetic stimulation is high attenuate vasoconstriction and activate the physiologically important response of vasomotion, that optimizes tissue blood flow.