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Understanding PI3K signalling in vessel growth and pathophysiology

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  • Title:
    Understanding PI3K signalling in vessel growth and pathophysiology
  • Author: Kobialka, Piotr
  • Subjects: Biologia molecular ; Biología molecular ; Blood vessels ; Cardiovascular system ; Cell physiology ; Cellular signal transduction ; Ciències de la Salut ; Cultius cel·lulars humans ; Cultivos celulares humanos ; Factor de crecimiento endotelial vascular ; Factor de creixement de l'endoteli vascular ; Fisiologia cel·lular ; Fisiología celular ; Human cell culture ; Molecular biology ; Sistema cardiovascular ; Transducció de senyal cel·lular ; Transducción de la señal celular ; Vascular endothelial growth factors ; Vasos sanguinis ; Vasos sanguíneos
  • Description: Programa de Doctorat en Biomedicina [eng] Our knowledge on the molecular basis behind physiological angiogenesis has significantly expanded in the last two decades. This progress also led to improvement in understanding of many vascular-related diseases in which angiogenesis is pathologically altered. Among many molecular regulators of angiogenesis, a family of lipid kinases called phosphatidylinositol 3-kinases (PI3Ks) occupies an important position in controlling endothelial cell functions. Indeed, numerous studies showed that endothelial cells are highly sensitive to fluctuations in the levels of phospholipids generated by these enzymes. Although highly conservative, the eight PI3K isoforms can produce three different types of phospholipids and this phenomenon formed the basis of the division into three different classes. Two members, ass I PI3Kα and ass II PI3K-C2α, are essential for proper vascular development. Moreover, somatic activating mutations in the gene encoding PI3Kα (PIK3CA) were found to cause 25% of venous malformations – a non-malignant, painful and mainly pediatric vascular disease for which the treatment options are limited. The vascular function of other isoforms, in particular class II PI3K-C2β, remains enigmatic. This is surprising given that this isoform is also express in cultured endothelial cells. This thesis is composed of two principal objectives objectives which together have been conceived to increase our knowledge on PI3K signaling in the endothelium. In the first part I evaluated the therapeutic efficacy of pan-AKT inhibitor, miransertib, in Pik3ca-driven vascular malformations using a preclinical mouse model. I showed that miransertib significantly prevents and reverts Pik3ca associated vascular hyperplasia through inhibition of endothelial cell proliferation. My results provide rationale for the therapeutic intervention of miransertib in treating patients with vascular malformations. The second part of the thesis studies the impact of PI3K-C2β isoform on blood vessel expansion and endothelial cell biology. Using both in vivo and in vitro models, I demonstrated for the first time that PI3K-C2β regulates retinal vascularity and vessel width, most likely as result of elevated vascular mTORC1 activity. Moreover, PI3K-C2β kinase inactivation led to increased collagen IV deposition and more stable vascular connections. In parallel, we showed that blood vessel-associated pericytes express high levels of PI3K-C2β and that its loss of function alters their morphology. Finally, we addressed the role of PI3K-C2β in the pathological neoangiogenesis associated with oxygen-induced retinopathy.
  • Publisher: Universitat de Barcelona
  • Creation Date: 2023
  • Format: 112
  • Language: English
  • Source: TDX Theses and Dissertations Online
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