Functional investigation of the coronary artery disease associated gene SVEP1 in vascular smooth muscle contraction

Large-scale genetic association studies have been successful in identifying the genetic contribution to coronary artery disease (CAD).

However, for the majority of loci the mechanisms leading to increased disease risk are unclear and careful experimental examination is required to translate genetic association to causal biology and new treatment targets. We recently identified an association between a low-frequency coding variant in SVEP1 and increased risk of CAD.

A proportion of this association can be attributed to the effect of the same variant on blood pressure (BP).

We have identified SVEP1 expression within the vascular smooth muscle layer of blood vessels, and demonstrated that inhibition of SVEP1 enhances contraction to key vasoconstrictors. These data suggest SVEP1 reduces vascular hyper-contractility through an unidentified mechanism.

We propose a comprehensive study using in vitro human vascular smooth muscle cells, ex vivo blood vessel functional studies and in vivo BP analyses to determine the molecular, cellular, and tissue effects driving regulation of vascular tone by SVEP1 and the CAD-associated genetic variant.

The proposed study will delineate the mechanistic role of SVEP1 in vascular smooth muscle contraction and answer whether modulation of SVEP1 signalling could provide a new therapeutic strategy for treating high BP and CAD.