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Le rôle des adhésions focales des cellules musculaires lisses vasculaires dans la rigidité artérielle et ses liens avec la coagulation

Abstract : Arterial stiffness increase is a major risk factor in the development of cardiovascular pathologies. It involves complex mechanisms corresponding to the rigidity of each element of the arterial wall. In the media, interactions between vascular smooth muscle cells (VSMC) and extracellular matrix (ECM) are mediated by αvβ3 integrin and focal adhesions (FA) which allow mechanotransduction. VSMCs have several physiopathological roles, they are involved in myogenic tone and arterial motility, and our laboratory has also demonstrated its role in coagulation, in particular via αvβ3 as a prothrombin receptor. Our hypothesis is that integrin is involved in the response of VSMCs in arterial stiffness and its pathophysiological mechanisms. The objectives of this work were to study the adaptation of VSMCs to ECMs with different rigidities and the impact of these modifications on cell and vascular physiology. The results of this work show that the rigidity of VSMCs increases with the rigidity of the ECM. The synthesis of proteins involved in AF and phosphorylation of focal adhesion kinase (FAK) were increased with the stiffness of the support. Functionally with the example of coagulation, the thrombin generation thrombin on the VSMCs surface decreases with increasing rigidity, and the use of an integrin inhibitor of αvβ3 further limits thrombin generation. Finally, we observed in human atherosclerotic aortas a co-localization of von Willebrand factor (VWF) and VSMCs and demonstrated a proliferative role of VWF on VSMCs via αvβ3. This function was confirmed in a VWF-deficient mouse model. The invalidation of this integrin in a mouse model (αsmKO) treated with angiotensin II (Ang II) we measured aortic arterial stiffness similar to the control, however the cellular stiffness of the αsmKO VSMC’s treated with Ang II was significantly more important. These results showed the major role of αvβ3 i ntegrin in the cellular biology of VSMCs, and in their adaptations to external stimuli such as rigidities of the ECM in their functions by inducing a decrease in the ability to support thrombin generation or in participating in their proliferation via the VWF. In conclusion, CMLVs, through its many roles, play a role on many scales in pathologies linked to aging. αvβ3 integrin is involved in many pathways of different functions and could be a therapeutic target of choice in order to modulate the responses of the arterial wall in aging.
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Submitted on : Wednesday, June 22, 2022 - 4:52:07 PM
Last modification on : Thursday, June 23, 2022 - 11:57:01 AM


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  • HAL Id : tel-03702049, version 1


Alexandre Raoul. Le rôle des adhésions focales des cellules musculaires lisses vasculaires dans la rigidité artérielle et ses liens avec la coagulation. Cardiologie et système cardiovasculaire. Université de Lorraine, 2021. Français. ⟨NNT : 2021LORR0294⟩. ⟨tel-03702049⟩



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