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Vascular endothelium: fit for purpose - understanding the molecular basis for organ-specific regulation of vascular function (Cristina Branco, Randall Johnson)

Supervisors: Cristina Branco, Randall Johnson

The vasculature is the preferred transport system for most compounds and cells, but also an exceptionally versatile organ, with broad and intricate ability to adjust to internal and external environmental cues, to respond and produce signals, recruit and interact differently with other cells, and function both as a barrier and a selective filter, all in accordance with the organ-specific needs at a given time. Different capillary beds, built of the same cellular components, have specific and unique properties, including a wide range of flow capacity and permeability. What regulates these differences is yet unclear, and there is plenty to discover on what determines the way endothelial cells proliferate, migrate, interact and adhere to form different kinds of vessels and networks, such as a continuous or a sinusoid capillary, for example. The aim of this project is to identify the molecular players involved in this regulation.

One essential participant in vascular endothelial cell function is the vascular endothelial growth factor (VEGF). This protein exists in several variants, each with preferential roles and uniquely perceived by downstream receptors with autocrine and paracrine consequences; even though these isoforms have been characterised in specific pathological and developmental contexts, the question remains if they contribute to the functional disparity of specific capillary beds; Is endothelial physiology regulated by endothelial cell molecular configuration and/or driven by microenvironmental cues: organ shaping the vasculature, or the vasculature defining organ function?

We propose to (1) dissect the molecular and biochemical characteristics of different endothelium types, underlying their morphology and function; and (2) identify the regulatory pathways upstream of their functional divergence.

These studies, even though not to be performed in the context of any specific pathology, will be critical in providing a strong foundation to predict disease incidence and progression, such as in hypertension, cancer, inflammation, wound healing, or adaptation to external environmental cues. Understanding the role and the function of this vital network can aid both in the identification of pathological risk factors, and of alternative or additional therapeutic avenues to explore in a myriad of contexts, from tumor dispersion, to auto-immune disease, or drug delivery.

Relevant references

  1. Grunstein J, Masbad JJ, Hickey R, Giordano F, Johnson RS (2000). Isoforms of vascular endothelial growth factor act in coordinate fashion to recruit and expand tumor vasculature. Mol Cell Biol. Oct;20(19):7282-91.

  2. Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D, Ellies L, Johnson RS (2012). Cancer Cell. Jan 17;21(1):52-65. doi: 10.1016/j.ccr.2011.11.017.

  3. Guyot M and Pagès G (2015). VEGF Splicing and the Role of VEGF Splice Variants: From Physiological-Pathological Conditions to Specific Pre-mRNA Splicing. Lorna Fiedler (ed.), VEGF Signaling: Methods and Protocols, Methods in Molecular Biology, vol. 1332, © Springer Science+Business Media New York 2015


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