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Theses

Extracellular matrix remodeling and angiogenesis : impact of the lysyl oxidase like-2 protein

Abstract : Angiogenesis is associated with extracellular matrix (ECM) remodeling. We previously showed that endothelial cells express the lysyl oxidase-like 2 (LOXL2) in vascular development and ischemic contexts, whichregulates both ECM deposition and angiogenesis.The molecular mechanisms connecting LOXL2 function in ECM assembly to angiogenesis however remained to be investigated. We firstused high-resolution structural analysis of cell-derived ECM and TIRF microscopy to characterize the succession of molecular events leading to ECM deposition and scaffolding. Incorporation of LOXL2 in fibronectin microfibrils generated the first structural elements before generation of a more complex network through association with self-assembled collagen IV.LOXL2 depletion impacted organization of such ECM supramolecular complexes by impairing fibronectin association to the collagen IV network, resulting in defectiveECM topography and mechanical properties. We aimed to decipher the mechanical response of endothelial cells to the ECM they generated. The intrinsic mechanotransduction properties of endothelial cellswere not altered by LOXL2 depletion. Long-term maturation of focal adhesions was nonetheless impaired in response to the defective ECM, resulting in defects in cytoskeleton remodeling, changes in cell shape and failure to redistribute adhesion proteins from cell-ECM to cell-cell adhesions. Altogether, these data provide new insights into ECM scaffolding and define LOXL2 as a key regulator of this process in endothelial cells. This autocrine mechanism confers the conditions mandatory for cytoskeleton remodeling and stabilization of cell-cell junctions required for angiogenesis.
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Submitted on : Monday, December 6, 2021 - 1:02:31 AM
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  • HAL Id : tel-03466541, version 1

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Marion Marchand. Extracellular matrix remodeling and angiogenesis : impact of the lysyl oxidase like-2 protein. Cellular Biology. Sorbonne Université, 2020. English. ⟨NNT : 2020SORUS138⟩. ⟨tel-03466541⟩

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