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Dr Andy Grant

2013 pump priming award recipient

Dr Andy Grant, King's College London

Investigating the contribution of transient receptor potential vanilloid 4 (TRPV4) to vascular dysregulation during sepsis.

Sepsis and septic shock are the leading causes of mortality in non-coronary intensive care units worldwide. Sepsis is a systemic inflammatory response syndrome triggered by infection (primarily bacterial) that can progress to septic shock, encompassing cardiovascular collapse, insufficient tissue perfusion and multi-organ failure. Clinical trials of potential interventions have been disappointing and treatment options remain highly inadequate. Consequently there is a strong drive to improve pre-clinical models of septic shock to better understand the molecular pathophysiology, facilitating the identification and screening of novel therapeutic interventions.

The cation channel TRPV4 is expressed in vascular endothelial cells. It is activated by endogenous stimuli such as shear stress and acetylcholine, leading to vasodilatation through stimulation of nitric oxide release or direct hyperpolarisation of vascular smooth muscle. Excessive TRPV4 activation leads to local vessel dysfunction, profound hypotension and circulatory collapse in mice. However TRPV4 effects on whole animal haemodynamics have been poorly studied, and the link between TRPV4 activity and vascular pathology has not been explored.

Our preliminary studies in cultured murine and bovine endothelial cells data suggest that TRPV4 activity is increased by exposure to bacterial products or inflammatory cytokines linked to sepsis. We therefore hypothesise that exposure to bacterial products / inflammatory cytokines during sepsis causes excessive activation of TRPV4. In turn, dysregulation of TRPV4-dependent vasorelaxation contributes to the cardiovascular collapse observed clinically. To fully understand the role of this channel in regulating systemic vascular function, in vivo model systems are required.

In this project we will undertake preliminary studies comparing the cardiovascular phenotype of TRPV4 knockout mice to wild type mice with or without a TRPV4 selective antagonist, in order to assess the effects on blood pressure and microcirculatory flow, under naïve and septic conditions.