Role of the Net1 exchange factor in the control of arterial tone and hypertension – NET

High blood pressure (BP) is still a major risk factor for cardiovascular morbidity and mortality. Hypertension is associated with physiological and biochemical changes in the vessel wall, characterized by excessive contraction, growth and proliferation of smooth muscle cells.
Increasing evidence implicate over-activation of Rho proteins, which control smooth muscle proliferation and contraction, as a common component for the pathogenesis of several cardiovascular disorders including hypertension. Recent advances in Rho protein signaling research indicate that the Rho exchange factors (Rho GEFs) are major regulators of Rho protein activity. In addition, linkage analyses studies have recently identified Rho GEFs as susceptibility genes for cardiovascular diseases. Our working hypothesis is that, as upstream activators of Rho proteins, Rho GEFs expressed in cardiovascular cells are good candidate targets for the treatment of cardiovascular disorders.
By combining basic research in cell and animal models, molecular, biochemical and functional analyses in vitro and in vivo, our objective is to validate Rho GEFs as new targets for future antihypertensive therapies.
Among the 28 RhoA GEFs expressed in arterial smooth muscle cells, we have identified two proteins, Net1 and P115, that play a key role in the effect of angiotensin II (Ang II) on arterial contraction and RhoA activity in vascular smooth muscle cells. We have recently addressed in detail the role of P115 and its involvement in hypertension (Guilluy et al., Nat Med, 2010).
The precise role of Net1 in the control of vascular tone and hypertension, as well as its link with P115 remains to be determined and these questions constitute the basis of our present project.
The aims of the present project are to:
- understand the role of Net1 in vascular smooth muscle cells;
- identify its relationships with P115 and P115-induced RhoA activation in vascular smooth muscle cells;
- determine the molecular components of the Net1/RhoA protein complex and their role in Ang II-mediated RhoA activation and RhoA-dependent functions;
- define in vivo the role of Net1 in the regulation of blood pressure and hypertension and validate Net1 as therapeutic targets for future treatments of hypertension by the use of inducible and smooth muscle specific Net1 knock-out mice.