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Endothelial regulation of organ-specific vascular function

Supervisor: Cristina Branco, Randall Johnson

Increasing evidence suggests that autocrine and paracrine factors released by endothelial cells (ECs) regulate organ homeostasis and orchestrate tissue regeneration. Ultimately, local control of blood flow (transport along blood vessels) and of substance delivery (transport across the endothelium) is heavily regulated by EC physiological status. Together, the transport and the molecular signaling mediated by the vascular system highlight the importance of capillary networks in organ function and dysfunction (pathology).

VEGFA plays a central role in the VEGF signaling, participating in both physiological (e.g. angiogenesis) and pathological processes (e.g. cancer). VEGFA, in particular, is translated in several splice variants with distinct receptor affinity and solubility. In humans, the most relevant are VEGF121, VEGF165 and VEGF189.

In response to hypoxia, the hypoxia-inducible factor (HIF) proteins up-regulate VEGFA expression, which can be mediated, in ECs, by the inducible nitric oxide synthase (iNOS). Regulation of most endothelial cell functions, from proliferation to integrity, permeability or ability to establish organised networks lies heavily downstream of the Vascular Endothelium Growth Factor A (VEGF-A), and we have shown that the autocrine role of each isoform contributes to different parameters of endothelial function.

The expression of each isoform is tissue-specific, and we now hypothesise if differential isoform expression underlies the EC heterogeneity seen across different organs. We aim to understand the contribution of VEGF A isoforms to the origin and maintenance of specialised capillary networks and how that correlates with organ performance as well as organ failure and predisposition for a number of pathological conditions.

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