Vascular Medicine

As many of the mechanisms controlling microvascular haemodynamics are unknown, the unit takes the approach of identifying key regulatory parameters in health before exploring these in disease states. The research group has interest in several disease states. These include insulin resistance, diabetes and conditions associated with increased microalbuminuria such as asymptomatic proteinuria, hypertension and rheumatoid arthritis. The team has an international reputation for its work exploring the microvascular abnormalities in patients with diabetes or at risk of diabetes. In this group it appears that the microcirculation is abnormal even in those at risk indicating that this is an extremely early, perhaps innate, abnormality.

Progressing this work further we have been exploring whether interventions known to influence insulin sensitivity, have an effect on the microcirculation. For example: insulin sensitivity may be modified by exercise or by therapy such as Pioglitazone. One of many mechanisms by which insulin sensitivity may be influenced involves alterations in the microcirculatory blood flow. If microvascular blood flow responses in muscle are increased by an intervention, insulin and glucose delivery may be improved and insulin sensitivity increased. It has been suggested that such increases in blood flow may be due to the endothelial dependent factor, nitric oxide and to explore this further we have been investigating whether Sildenafil, a drug which enhances the action of nitric oxide, is effective in altering insulin sensitivity and microvascular blood flow.

As part of our investigations of normal physiology, we are interested in the microcirculatory changes which take place during the ageing process. In this regard we have been exploring whether the endothelial layers become dysfunctional using both in vivo and in vitro techniques to examine responses of human small vessels.

The ageing process appears to be associated with changes in endothelial function, such that those who maintain normal blood pressure have an enhanced NO responsiveness. Capillary pressure is increased by the ageing process particularly as women move from the pre-menopausal to the post- menopausal state and one of our present investigations is exploring the effect of HRT in both healthy women and type two diabetic women.

As part of a collaborative programme with Professor Nish Chaturvedi of Imperial College London, abnormalities of the microvascular function are being explored in different ethnic groups, groups which are clearly identified as having differences in cardiovascular risk.

This therefore explores further the suggestion that microvascular dysfunction may play a key role in macrovascular disease processes and would advance our understanding significantly in this area.

The leakiness of the lining of blood vessels can influence the movement of macromolecules out of blood into vessel walls and thus the development of atherosclerosis. In addition the movement of fluid from the intravascular to the extra vascular compartment can lead to oedema formation or in less severe cases an increase in the oxygen diffusion distance and thus abnormality of the tissue nutrition.

We have been exploring whether conditions associated with increased leakage of albumin from the kidney such as asymptomatic proteinuria and rheumatoid arthritis are associated with systemic abnormalities of capillary permeability and the mechanisms underlying such abnormalities.

This collaboration with Professor Hattersley and Dr Frayling explores the role of genetic polymorphisms on microvascular function.

The unit is keen to develop both in vivo and in vitro mechanistic studies and to this end collaborates very closely with Cell and Molecular Biology. The unit has an interest in exploring both ex-vivo functions of microvessels taken from man as well as cultured human endothelial cells. It also collaborates very closely in this regard with the Medical Physics Department with whom we are exploring the role of the surface layers of the endothelium, the glycocalyx, in collaboration also with the University of Warwick Chemistry Department, Professor Patrick Unwin and colleagues.

The unit has PhD, MD and MPhil students.