Regulation of actomyosin contractility by p110α pi3-kinase in sprouting angiogenesis
- Autores: Ana Angulo Urarte
- Directores de la Tesis: Mariona Graupera García Milà (dir. tes.), Francesc Vinyals Canals (tut. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Susana de la Luna Gargantilla (presid.), Stephan Huveneers (secret.), Rui Benedito (voc.)
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Class IA PI3K (PI3K) functions have been widely investigated over the last two decades. PI3K signalling is located at the crossroads of many cell surface receptors sending signals to coordinate multiple cellular functions such as cell growth, survival, motility, and metabolism. Fine-tune regulation of PI3K signalling in cells is needed to ensure the functionality of tissues and organs. However, it is still not clear how or even which PI3K isoforms are concerted into precise morphogenic events. On the other hand, PI3K activity plays central roles in several cellular processes critical for cancer progression. Hence, PI3K pathway inhibition is considered an important target for therapeutic intervention in cancer, and progress in the clinical area is being monitored by many clinical trials with PI3K inhibitors.
We were interested in investigating the role of PI3K activity in endothelial cells during the process of angiogenesis. Although ECs express all class I PI3K isoforms, only inactivation of the catalytic subunit p110α in endothelial cells (not p110β or p110δ inactivation) leads to vascular defects in the embryo (Graupera et al. 2008). This indicates that p110α activity in ECs is required in a cell-autonomous manner to ensure proper vascular development and remodelling during the embryogenesis. However, progress in the understanding of how p110α-PI3K signalling regulates the different steps of vascular morphogenesis has been hampered by embryonic lethality that both the constitutive and endothelial specific p110α mutant mice exhibit.
By using a tamoxifen-inducible endothelial Cre line in mouse and genetic and pharmacological approaches in zebrafish embryos, we have found that p110α signalling is required to maintain vessel stability. The lack of p110α activity leads to endothelial tubular structures composed of single cells that show an elongated shape with multiple protrusions and no lumen. These ECs fail in the elongation of the inter-endothelial contacts during the sprout outgrowth. Furthermore, I found that p110α is involve in the initial steps of fusion and is necessary for proper establishment of a new connection. Finally, I identifyed that p110α negatively controls actomyosin contractility independently of Rho/ROCK signalling pathway and that this control could be exerted through the regulation of MLC phosphatase activity by the impact on mRIP and/or MYPT proteins.
