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FP7

STIFFMATRIXVASC Résumé de rapport

Project ID: 304162
Financé au titre de: FP7-PEOPLE
Pays: France

Periodic Report Summary 1 - STIFFMATRIXVASC (From extracellular matrix rigidity to vascular aging)

The extracellular matrix (ECM) affects many aspects of cell growth and behavior. Not only do cells respond to the composition of the ECM, but they also respond to its physical properties. Interestingly, this mechanical adaptation to ECM stiffness impacts on numerous cell functions, including growth, motility and differentiation and plays a role during tissue development and renewal. The cellular adaptation to ECM stiffness is especially of interest in the vascular system, where the large arteries from the central arterial system become stiffer with age. It is now well established that arterial stiffening significantly contributes to cardiovascular disease (CVD) development, such as coronary artery disease, hypertension and stroke. Recent studies have highlighted that ECM stiffness affects endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) differentiation, proliferation and motility, suggesting that the cellular response to ECM stiffness may play an important role during the development of aging-associated CVD. Whereas the pathological role of arterial stiffening has been well described, the molecular mechanisms that regulate VSMCs and ECs functions in response to ECM stiffening are unknown.
We recently showed that application of external force on integrin-based adhesion activates the small GTPase RhoA, which in turn regulates adhesion maturation and growth. By combining biochemical and biophysical approaches, we identified LARG and GEF-H1, as key upstream regulators that mediate force-dependent RhoA activation. Interestingly, we found in preliminary results that the same pathways are activated when cells are grown on rigid substrates, suggesting that LARG and GEFH1 may also regulate the mechanical response to ECM stiffness.
All these observations raise three questions: Do LARG and GEF-H1 regulate the mechanical response to ECM stiffness? Do LARG and GEF-H1 contribute to the change in proliferation, motility and differentiation observed when cells are grown on stiff surfaces? Are LARG and GEF-H1 modulated during arterial stiffness? To answer these questions we have designed a proposal in three phases with the following objectives:
1. To analyze the involvement of LARG and GEF-H1 during the mechanical response to ECM stiffness.
2. To evaluate the contribution of LARG and GEF-H1 to the defects in migration, proliferation and differentiation observed when VSMCs and ECs are grown on stiff substrates.
3. To analyze the activity and expression of LARG and GEF-H1 during arterial stiffening.

Results for the first period.
We identified the molecular mechanism that activates GEF-H1 in response to matrix rigidity. We found that RasGRFs are activated in response to matrix rigidity and in turn activates a GEF-H1/RhoA pathway. Additionally, we analyzed the cellular mechanical response to matrix rigidity and observed that RasGRF depletion altered adhesion size and strength. Interestingly, we found that RasGRF knockdown did nopt affect migration, but prevented VSMC survival stimulation in response to matrix rigidity. This result indicates that RasGRF could potentially participate to age-associated vascular remodeling and contribute to CVD. This will be tested during the last period of the project.

Contact

Mélanie MOLIERE, (Financial adminstrator)
Tél.: +33 2 40358679
Fax: +33 2 40477701
E-mail
Numéro d'enregistrement: 184202 / Dernière mise à jour le: 2016-06-08
Source d'information: SESAM