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Thesis

French

ID: <

10670/1.z9p50w

>

Where these data come from
Role of CD31 in the outcome of acute cardiovascular injuries

Abstract

CD31 also called PECAM-1 (Platelet Endothelial Cell Adhesion Molecule-1) is a 130-kDa single pass transmembrane glycoprotein composed of 6 extracellular Ig-like domains and a cytoplasmic tail with two ITIMs motifs (Immunoreceptor Tyrosine based Inhibitory Motifs). The CD31 trans-homophilic receptor is exclusively and constitutively expressed by endothelial cells, platelets and all leukocytes and play a crucial role in cells regulation at blood-vessel interface.Upon sequential phosphorylation, the two ITIMs of CD31 promote phosphatase-dependent pathway while tyrosine/inositol-dependent pathway is uncoupled. Thus, activator or inhibitor CD31 effect depends on cell type. CD31 engagement drives mutual cell-cell detachment signals and raises the activation threshold of CD31+ cells, globally acting as a negative co-signaling receptor on platelet and leukocytes. The case is different for the endothelial cells, which adhere on their basal membrane and establish permanent CD31-CD31 interactions at their lateral borders. Indeed, the permanent trans-homophilic interaction of CD31 molecules engaged at the cell-cell junctions of the adherent endothelial cells and their basal serine phosphorylation may account for the prevalent positive effect on endothelial cell survival and physiologic functions. Regulation of endothelial, platelet and leukocyte interactions by CD31 may be particularly important during biological responses that develop following cardiovascular injury.To evaluate this hypothesis, I studied during my thesis the role of CD31 in the outcome of aortic dissection and myocardial ischemia reperfusion, two clinical conditions related to acute and high life-threatening lesions not only immediately but also in the long term, if tissue remodeling is not appropriate. My work has shown that the function of CD31 is important in the outcome of acute cardiovascular lesions: it promotes the return to homeostasis in the microcirculation to ensure perfusion of the injured tissue but it also actively contributes to the tissue repair, in particular favoring the acquisition of a repair phenotype by the leucocytes infiltrated at the lesion sites. In the case of aortic dissection, our results show that the function of CD31 is crucial to allow rapid resorption of the hematoma and the formation of a collagen-rich scar in the arterial lesion thus preventing aneurysmal evolution and the risk of rupture of the aorta. In the case of myocardial infarction, the effectiveness of recanalization procedures depends on the restoration of microvascular circulation. Indeed, the survival of each heart muscle fiber will depend on its own capillary. In CD31 KO mice, we found that the response of platelets, leukocytes, and endothelium within the microcirculation in the infarct area is inappropriate. Thus, in the absence of CD31, dysfunction of the blood cells interacting with the endothelium in microcirculation prevents tissus reperfusion. This phenomenon, also known as "no-reflow", corresponds to an absence of microvascular reperfusion despite the re-opening of the occluded artery and results in an enlargement of necrosis zone.Thus, the regulatory functions of CD31 seem to play a particularly determining role in the outcome of acute lesions of the cardiovascular system, where hemodynamic stresses make the tissue repair even more difficult and urgent.

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