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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
Authors: Kobialka, Piotr
Contributors: University/Department: Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
Thesis Advisors: Graupera i Garcia-Milà, Mariona, Viñals Canals, Francesc
Source: TDX (Tesis Doctorals en Xarxa)
Publisher Information: Universitat de Barcelona, 2020.
Publication Year: 2020
Physical Description: 112 p.
Subject Terms: Factor de creixement de l'endoteli vascular, Factor de crecimiento endotelial vascular, Vascular endothelial growth factors, Transducció de senyal cel·lular, Transducción de la señal celular, Cellular signal transduction, Biologia molecular, Biología molecular, Molecular biology, Cultius cel·lulars humans, Cultivos celulares humanos, Human cell culture, Vasos sanguinis, Vasos sanguíneos, Blood vessels, Sistema cardiovascular, Cardiovascular system, Fisiologia cel·lular, Fisiología celular, Cell physiology, Ciències de la Salut
Description: Programa de Doctorat en Biomedicina
Description (Translated): [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.
Document Type: Dissertation/Thesis
File Description: application/pdf
Language: English
Access URL: http://hdl.handle.net/10803/688639
Rights: L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/
Accession Number: edstdx.10803.688639
Database: TDX
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  Data: Understanding PI3K signalling in vessel growth and pathophysiology
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  Data: University/Department: Universitat de Barcelona. Facultat de Medicina i Ciències de la Salut
– Name: Author
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  Data: Graupera i Garcia-Milà, Mariona<br />Viñals Canals, Francesc
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  Data: TDX (Tesis Doctorals en Xarxa)
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  Data: Universitat de Barcelona, 2020.
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  Data: 112 p.
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  Data: <searchLink fieldCode="DE" term="%22Factor+de+creixement+de+l'endoteli+vascular%22">Factor de creixement de l'endoteli vascular</searchLink><br /><searchLink fieldCode="DE" term="%22Factor+de+crecimiento+endotelial+vascular%22">Factor de crecimiento endotelial vascular</searchLink><br /><searchLink fieldCode="DE" term="%22Vascular+endothelial+growth+factors%22">Vascular endothelial growth factors</searchLink><br /><searchLink fieldCode="DE" term="%22Transducció+de+senyal+cel·lular%22">Transducció de senyal cel·lular</searchLink><br /><searchLink fieldCode="DE" term="%22Transducción+de+la+señal+celular%22">Transducción de la señal celular</searchLink><br /><searchLink fieldCode="DE" term="%22Cellular+signal+transduction%22">Cellular signal transduction</searchLink><br /><searchLink fieldCode="DE" term="%22Biologia+molecular%22">Biologia molecular</searchLink><br /><searchLink fieldCode="DE" term="%22Biología+molecular%22">Biología molecular</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+biology%22">Molecular biology</searchLink><br /><searchLink fieldCode="DE" term="%22Cultius+cel·lulars+humans%22">Cultius cel·lulars humans</searchLink><br /><searchLink fieldCode="DE" term="%22Cultivos+celulares+humanos%22">Cultivos celulares humanos</searchLink><br /><searchLink fieldCode="DE" term="%22Human+cell+culture%22">Human cell culture</searchLink><br /><searchLink fieldCode="DE" term="%22Vasos+sanguinis%22">Vasos sanguinis</searchLink><br /><searchLink fieldCode="DE" term="%22Vasos+sanguíneos%22">Vasos sanguíneos</searchLink><br /><searchLink fieldCode="DE" term="%22Blood+vessels%22">Blood vessels</searchLink><br /><searchLink fieldCode="DE" term="%22Sistema+cardiovascular%22">Sistema cardiovascular</searchLink><br /><searchLink fieldCode="DE" term="%22Cardiovascular+system%22">Cardiovascular system</searchLink><br /><searchLink fieldCode="DE" term="%22Fisiologia+cel·lular%22">Fisiologia cel·lular</searchLink><br /><searchLink fieldCode="DE" term="%22Fisiología+celular%22">Fisiología celular</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+physiology%22">Cell physiology</searchLink><br /><searchLink fieldCode="DE" term="%22Ciències+de+la+Salut%22">Ciències de la Salut</searchLink>
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  Data: Programa de Doctorat en Biomedicina
– Name: Abstract
  Label: Description (Translated)
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  Data: [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.
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  Data: L'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/
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RecordInfo BibRecord:
  BibEntity:
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 112
    Subjects:
      – SubjectFull: Factor de creixement de l'endoteli vascular
        Type: general
      – SubjectFull: Factor de crecimiento endotelial vascular
        Type: general
      – SubjectFull: Vascular endothelial growth factors
        Type: general
      – SubjectFull: Transducció de senyal cel·lular
        Type: general
      – SubjectFull: Transducción de la señal celular
        Type: general
      – SubjectFull: Cellular signal transduction
        Type: general
      – SubjectFull: Biologia molecular
        Type: general
      – SubjectFull: Biología molecular
        Type: general
      – SubjectFull: Molecular biology
        Type: general
      – SubjectFull: Cultius cel·lulars humans
        Type: general
      – SubjectFull: Cultivos celulares humanos
        Type: general
      – SubjectFull: Human cell culture
        Type: general
      – SubjectFull: Vasos sanguinis
        Type: general
      – SubjectFull: Vasos sanguíneos
        Type: general
      – SubjectFull: Blood vessels
        Type: general
      – SubjectFull: Sistema cardiovascular
        Type: general
      – SubjectFull: Cardiovascular system
        Type: general
      – SubjectFull: Fisiologia cel·lular
        Type: general
      – SubjectFull: Fisiología celular
        Type: general
      – SubjectFull: Cell physiology
        Type: general
      – SubjectFull: Ciències de la Salut
        Type: general
    Titles:
      – TitleFull: Understanding PI3K signalling in vessel growth and pathophysiology
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            NameFull: Kobialka, Piotr
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              Type: published
              Y: 2020
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