Flt1 at the neuro-vascular interface

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The vascular network closely associates with the neuronal network throughout embryonic development, in adulthood and during tissue regeneration. Close association of vessels and neuronal networks allows reciprocal cross-talk involving diffusible molecules, which is important for physiological functions in both domains. Disturbances herein associate with neurodegenerative diseases, neuropathy, and cardiovascular disorders.Formation of vascular and neuronal networks shows many similarities including common molecular cues and the principle of directed guidance. In the vascular system, Vegf-a acts as the major regulator of angiogenesis and sprout guidance. In the neuronal system, Vegf-a can have direct effects on neurons and modulate processes such as neuronal survival and axon guidance. Vegf receptor-1 (Flt1) mainly acts as a Vegf-a decoy receptor, thereby limiting Vegf-a bio-availability and signaling through Vegf receptor-2 (Kdr). Flt1 is expressed in both vessels and nerves and therefor uniquely endowed with the dual ability to affect growth of vessels and nerves. We hypothesize that Flt1 plays a central role in neuro-vascular communication. In line with this hypothesis we found that spinal cord vascularization in zebrafish proceeds from veins involving two-tiered regulation of neuronal soluble Flt1 (sFlt1) and Vegfaa via a novel sprouting mode termed tertiary sprouting. Here we propose to analyze the molecular mechanism driving tertiary sprout initiation, sprout guidance and the selective anastomosis formation with arteries. Pilot data suggest that tertiary sprouts sample their targets and preferentially anastomose with Neuropilin-1 (Nrp1) expressing endothelium in specific arterial domains. Mechanistically, neuronal Plgf acts as a positive regulator of this process. Plgf provokes displacement of Vegfaa from arterial Nrp1, thereby augmenting Vegfaa around arteries, promoting arterial Kdrl signaling and filopodia formation, an endothelial feature that critically determines the propensity to form an anastomosis.During spinal cord development, stem and progenitor cells differentiate into mature neurons, a process that is paralleled by a change from glycolytic toward more aerobic tissue metabolism, and increased vascularization. Here we propose to analyze how the extent of spinal cord vascularization controls the switch of stem cell expansion to differentiation either via changes in metabolism or angiocrine signals. To test this we created a series of transgenic and mutant zebrafish with either hyper vascularized or hypo vascularized spinal cords based on modulation of sFlt1 and Vegfaa levels at the neuro-vascular interface. Using single cell sequencing and RNA tomo-seq we will track changes in cell fate specification in a spatio-temporal manner. Preliminary data show reduced progenitor pools in the hyper vascularization scenarios, consistent with blood vessel function determining neuronal differentiation.