Role of Plexin D1 in flow-induced atherosclerosis progression

Atherosclerosis is a highly complex disease that is determined by a combination of local haemodynamic and systemic risk factors.

Low and disturbed shear stress is a major determinant not only of initiation of atherosclerosis but also of transition to vulnerable and high-risk plaques in humans.

Despite intense efforts, current treatments have demonstrated limited efficacy in slowing down plaque progression, thereby underscoring the significance of identifying novel therapeutic targets in mechanically-induced disease pathogenesis.

We have recently identified the cell guidance receptor Plexin D1 (PlxnD1) as a driver of inflammatory EC activation and initiation of atherosclerosis in areas of disturbed flow.

We hypothesise that PlxnD1 is a central player in orchestrating flow responses that promote initiation and progression of atherosclerotic lesions at sites of atheroprone flow.

We propose complementary in vitro and in vivo aims which will increase our understanding of how PlxnD1 drives atherosclerosis progression to vulnerable plaques and identify potential critical regulators of EC pathology.

Understanding the disease-specific effects of PlxnD1 will establish the necessary basis for treatment strategies that can specifically target PlxnD1 for clinical benefit in atherosclerosis.