title: Neurovascular interactions in the spinal cord during embryonic development and pathology
creator: Da Cruz Vieira, Jose Ricardo
description: Formation and maintenance of such a highly specialized structure as the central nervous system requires the concomitantly cooperation between the vascular and neural systems. Interactions between these systems are necessary to instruct each other to correctly develop and achieve homeostatic conditions. Thus, understanding neurovascular communications during embryonic development and their alterations in pathology are fundamental.  	Here, I reveal a novel crosstalk occurring in the developing spinal cord between motor neurons (MNs) and endothelial cells (ECs) necessary to keep MN columns avascular for a certain period of time. From inferring and analyzing cell-to-cell communication from previously published single-cell RNA sequencing and, by using cell-specific knockout mice, I demonstrate that removal of semaphorin 3C (Sema3C) in MNs, or its receptor PlexinD1 in ECs, results in premature vascularization of MN columns. Furthermore, in vitro assays similarly show that removal of one of the factors in the respective cell results in increased contact between MNs and ECs. This premature vascular misspatterning leads to MN developmental defects such as impaired MN axon exiting the spinal cord at early stages. At later developmental stages, removal of PlexinD1 signaling in ECs leads to MN maturation defects. This study shows the importance of Sema3C-PlexinD1 signaling as a communication path between MNs and ECs during development. It also demonstrates that for proper spinal cord formation a timely and spatially controlled vascularization is fundamental. In the second part of my thesis, I provide additional evidence that highlights the importance of the neurovascular unit in pathology. My results suggest that ECs and their derived factors are involved in the development and/or maintenance of chronic pain. I show that persistent inflammatory pain or neuropathic pain lead to a temporal and local opening of the blood-spinal cord barrier (BSCB), even without major changes in the neurovascular structure. Furthermore, I demonstrate that leucine-rich α-2 glycoprotein 1 (Lrg1) is increased in ECs and in the bloodstream in pain conditions, and that it might be a potential regulator of BSCB permeability.  Overall, this thesis shows that interactions between neural and vascular cells are not only required to fine-tune embryonic CNS development, but that they also play a role in the regulation of pathologies, as I show for chronic pain. These results support the need of not only study such complex systems in isolation, but that research towards better understanding their inter-relationship is also important.
date: 2024
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/33342/1/PhDThesis_RicardoVieira_Final.pdf
identifier: DOI:10.11588/heidok.00033342
identifier: urn:nbn:de:bsz:16-heidok-333428
identifier:   Da Cruz Vieira, Jose Ricardo  (2024) Neurovascular interactions in the spinal cord during embryonic development and pathology.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/33342/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng