Gervaise Loirand

 

This program is particularly focused on (i) the regulation of RhoA by phosphorylation and (ii) the RhoA exchange factor Arhgef1, identified as a target of interest in hypertension and atherosclerosis.
It is divided in three axes:

  • RhoA phosphorylation and arterial remodelling (restenosis and atherosclerosis):
The regulation of RhoA by phosphorylation may represent a crucial component of the determinant actions of the endothelium on the arterial wall in normal and pathological conditions associated with endothelial dysfunction, reduction of NO bioavailability (Loirand, Physiol Rev, 2013). Indeed, in vivo, arterial RhoA is basally phosphorylated on Ser188 but the physiological consequences of this inhibitory RhoA phosphorylation remain unknown. To address this question, we have generated a mouse model expressing the phosphomimetic mutant S188E-RhoA. This model will be used to analyze cardiovascular functions in physiological or pathophysiological conditions. We hypothesize that S188E-RhoA-expressing mice would have reduced blood pressure and would be resistant to the development of systemic or pulmonary hypertension, remodelling and atherosclerosis. The development and the use of this model could thus help to define whether pharmacological targeting of Rho protein phosphorylation could have a clinical interest, particularly in the context of arterial diseases associated with over-activation of Rho proteins.
 
  • Arghef1 in ageing-associated arterial stiffness and hypercoagulability

Although systemic and local processes involved in age-induced arterial stiffness are complexes and still not well understood, a growing body of evidence points out causal and interdependent roles of the renin-angiotensin-system, inflammation, and vascular cells contractility. We have demonstrated that the RhoA exchange factor Arhgef1 mediates Ang II-induced RhoA activation and plays an essential role in the control of vascular tone, blood pressure and inflammation (Guilluy, Nat Med, 2010; Carbone, J Clin Invest, 2017). Our hypothesis is that Arhgef1 is involved in ageing-associated arterial stiffness and hypercoagulability. We use Arhgef1-deficient mice and cells to delineate the mechanisms by which Arhgef1/RhoA/Rho kinase signalling pathway participate in ageing-induced alterations in arterial structure and function, vascular cell and platelet responses to arterial wall stiffening.

  • Design and screening of Arhgef1 inhibitors

As we identified Arhgef1 as a relevant target for the development of new therapies against high blood pressure, our aim is to develop RhoA/Arhgef1 interaction-specific small-molecule inhibitors. This project is based on our collaboration with computational and medicinal chemists. We develop complementary approaches using both molecular modeling tools and pharmacophore-based in silico screening of chemical libraries to identify ligands targeting Arhgef1/RhoA interaction. Candidate ligands will be purchased or synthetized and their ability to inhibit RhoA activity will be assessed by relevant biochemical/biological in vitro assays. Structure of the best compounds will be examined and modified to optimize their affinity and inhibitory potency. Chemical series will be thus generated and tested in vivo in mouse models.

Publications

Leukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosis.
Carbone ML, Chadeuf G, Heurtebise-Chrétien S, Prieur X, Quillard T, Goueffic Y, Vaillant N, Rio M, Castan L, Durand M, Baron-Menguy C, Aureille J, Desfrançois J, Tesse A, Torres RM, Loirand G.
J Clin Invest 127: 4516–4526, 2017.
The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.
Guilluy C, Brégeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, Henrion D, Scalbert E, Bril A, Torres RM, Offermanns S, Pacaud P, Loirand G.
Nat Med 16: 183–190, 2010.
 
Small G proteins in the cardiovascular system: physiological and pathological aspects.
Loirand G, Sauzeau V, Pacaud P.
Physiol Rev 93: 1659–1720, 2013.

Funding

  • Fondation de France
  • I-SITE NExT
  • Région Pays de Loire
FDF
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