Vasso Kostourou research group

Research

Blood vessels are formed by two processes: Vasculogenesis which is the de novo synthesis of blood vessels from angioblasts and endothelial progenitor cells, and angiogenesis which entails the remodelling of already existing vessels and the development of new ones by sprouting and intussusceptions. To accomplish these events, endothelial cells are engaged in several processes including, extracellular matrix reorganisation, polarisation, lumen formation, proliferation and migration. Endothelial cells are connected with each other and attached to the extracellular matrix. Thus, alterations in their physiological status requires the translation of signals (chemical and mechanical) received by the extracellular environment and the appropriate re-organisation of their adhesion sites to modify existing blood vessels and enable the assembly of new ones. The molecular components of cell adhesion sites are diverse and include i) adhesion receptors such as integrins and cadherins, ii) cytoskeletal scaffolding molecules that link adhesion receptors to actin cytoskeleton (e.g. talin, zyxin, vinculin, ILK, PINCH), iii) GTPases and their effector molecules (e.g. Rho, Rac, cdc42, GEFs), and iv) signalling enzymes such as kinases (e.g. PI3K, FAK, Src, ROCK, PAK), phosphatases (e.g. PTP-1B, PTP-PEST, SHP2) and lipases.
Our research aims to identify the key molecular players that are crucial for endothelial cell adhesion remodelling and hence blood vessel formation and function. Our ongoing projects are focusing on adhesion molecules that associate with integrins and provide a molecular link to cytoskeleton such as talin, ILK and PINCH. Our approach utilises genetically modified mouse models and various cellular and molecular assays in primary endothelial cells and ex vivo tissues and seek to implement novel technologies and state-of-the-art approaches, such as live-imaging of adhesion site formation, 3D-cell culture systems, in vivo imaging, etc.

Cell-extracellular matrix adhesions in endothelial cell	Actin (red) and tubulin (green) cytoskeletal fibers in endothelial cell	Cell-cell contacts in endothelial cell monolayer

Endothelial cell adhesion dynamics and mechanotransduction
We are particular interested to examine the spatial and temporal molecular composition of cell adhesion sites and to identify the key regulators of adhesion remodelling and cell migration. In addition, using an interdisciplinary approach, involving biophysics and mathematical modelling, we investigate how forces generating by the extracellular environment are transmitted inside the cell and get translated into signals that guide cell movement.

Primary endothelial cells expressing paxillin-GFP (green), cherry-actin(red) and stained with anti-vinculin antibody (blue).	Primary endothelial cells expressing paxillin-GFP (green), zyxin-mRFP (red) and stained with phalloidine-Alexa 633 (blue).	Endothelial cells embedded in 3D matrices

Blood vessel morphogenesis during development
We are currently investigating the role of Talin and ILK in blood vessel formation during embryogenesis and retina development, using temporally- induced and tissue specific knock-out mice.

The mouse embryonic vasculature	Blood vessel formation in the developing retina.

Blood vessel function in disease
We aim to dissect the links between disorganised cell-cell and cell-extracellular matrix adhesion and blood vessel morphogenesis. Aberrant angiogenesis is the hallmark of cancer and metastasis and characterise various pathologies such as retinopathies, inflammatory and cardiovascular diseases. Identifying molecular targets that lead to enhanced or decreased angiogenesis could facilitate therapeutic interventions to be used accordingly, to modify the blood vessel supply, depending on the needs of the tissue and the pathological condition.

Abnormal angiogenesis in mouse retina	Blood vessel formation by endothelial cell sprouting from aortic rings.