Role of endothelial glycolysis in pericyte recruitment and function

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Rationale: The coordination of sprouting angiogenesis, the growth of new blood vessels, and specialization of endothelial cells (ECs) is essential for vascular patterning and the proper function of organs. The mouse retina's vascular network is unique, with one superficial and two deeper neuroretina layers, which start developing at birth. The neuroretina's homeostasis strongly depends on the highly selective blood-retina barrier (BRB), which is regulated by the interaction between the ECs and the surrounding pericytes (PCs). Despite its importance, the mechanisms regulating BRB formation during sprouting angiogenesis remain poorly characterized. Endothelial tip cells are specialized cells at the extremity of newly formed capillaries that guide capillary outgrowth. The retinal superficial tip cells (S-tip cells) do not interact with PCs and have a low BRB. We recently revealed that diving tip cells invading the mouse neuroretina (D-tip cells) are distinct from S-tip cells. D-tip cells have a unique transcriptional signature, including high TGFß signaling and low glycolysis rate. Compared with S-tip cells, D-tip cells show strong interaction with PCs and acquire BRB properties. Endothelial deletion of TGFß receptor I (Alk5iEKO) inhibits D-tip cell specification, BRB, and deep vascular plexus formation. Moreover, loss of endothelial Alk5 promotes tip cell glycolysis and aberrant pericyte differentiation. Mechanisms regulating tip cell-PC interaction remain unclear. S- and Alk5iEKO tip cells express more lactate dehydrogenase A (LDHA) than D-tip cells, suggesting that lactate produced by tip cells could regulate PC recruitment and function. Therefore, this proposal aims to investigate whether tip cell metabolism could control PC recruitment and BRB acquisition. Objective and hypothesis: To address this hypothesis, we propose three specific aims: 1) Investigate whether pericytes are essential for D-tip cell specification and neuroretina vascularization; 2) Determine whether tip cell glycolysis regulates pericyte recruitment and identity; and 3) Assess lactate-mediated pericyte identity and behavior. Relevance: Pericytes recruitment and function are essential for retina and brain angiogenesis, but mechanisms remain unclear. This study will allow us to propose a new comprehensive mechanism that regulates retina angiogenesis and will constitute the basis for future research in the field. Notably, the concept of sprouting angiogenesis and BRB formation coupling remains largely unexplored during retina and brain development. Therefore, identifying endothelial cues regulating PCs recruitment and function will be of great significance to fields beyond retina biology, such as organoid vascularization, and strategic interest to vascular research in Canada.