Wisniewski, Laura; (2020) P130Cas – a novel mediator for BMP2-driven venous angiogenesis in zebrafish. Doctoral thesis (Ph.D), UCL (University College London).

Preview	Text (Redacted) PhDthesis_LauraWisniewski_edited file.pdf Download (7MB) | Preview
	Video Movie_479_bcar1-30hpf.mp4 Download (3MB)
	Video Movie_481_WT-30hpf.mp4 Download (3MB)
	Video Movie_489_WT-48hpf.mp4 Download (2MB)
	Video Movie_493_bcar1-48hpf.mp4 Download (2MB)

Abstract

Sprouting angiogenesis, the formation of new blood vessels from existing ones, is critically involved in the cardiovascular development and homeostasis of all higher organisms. While much focus has been directed towards the molecular cues inducing and inhibiting angiogenesis, less research has investigated how endothelial cells transduce these signals and respond accordingly. Our group and others have shown that the adaptor protein P130CAS plays a pivotal role in mediating both endothelial cell and vascular smooth muscle cell proliferation and migration, in response to VEGF and PDGF signalling, respectively. Two in vivo studies in mice found it is absolutely required for embryogenesis as P130CAS-deficient mice die in utero due to cardiac failure or a dysfunctional vasculature. Despite these findings, no further in vivo studies have addressed the cardiovascular function of this adaptor protein. Here, I characterise a novel P130Cas deletion model in the zebrafish. Work presented in this thesis identifies that, in zebrafish, P130Cas activity is dispensable for heart organogenesis and arterial angiogenesis during development. Instead, I found that it is required for venous angiogenesis and lymphangiogenesis. I further present preliminary evidence that P130Cas mediates heart regeneration in the adult zebrafish following cryoinjury, likely through promoting coronary vessel growth. Mechanistically, I present evidence suggesting that in zebrafish, P130Cas mediates Bmp2-induced venous sprouting via Src family kinases. In absence of P130Cas, venous endothelial cells appear to not convert Bmp2b signalling effectively, they are impaired in their ability to form cell protrusions and dynamically detach from neighbouring endothelial cells. This thesis shows that P130Cas transduces venous-specific Bmp2b signalling during sprouting angiogenesis. It also identifies a role for P130CAS in cardiac regeneration, where it is required to replace fibrotic scar tissue with healthy myocardium.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item