Abstract
Blood vessels are vital to sustain life in all vertebrates. While it is known that mural cells (pericytes and smooth muscle cells) regulate vascular integrity, the contribution of other cell types to vascular stabilization has been largely unexplored. Using zebrafish, we identified sclerotome-derived perivascular fibroblasts as a novel population of blood vessel associated cells. In contrast to pericytes, perivascular fibroblasts emerge early during development, express the extracellular matrix (ECM) genes col1a2 and col5a1, and display distinct morphology and distribution. Time-lapse imaging reveals that perivascular fibroblasts serve as pericyte precursors. Genetic ablation of perivascular fibroblasts markedly reduces collagen deposition around endothelial cells, resulting in dysmorphic blood vessels with variable diameters. Strikingly, col5a1 mutants show spontaneous hemorrhage, and the penetrance of the phenotype is strongly enhanced by the additional loss of col1a2. Together, our work reveals dual roles of perivascular fibroblasts in vascular stabilization where they establish the ECM around nascent vessels and function as pericyte progenitors.
Highlights
IntroductionBlood vessels must rapidly expand and contract in response to systemic cues, and be sturdy to withstand the stress of blood flow
The vascular system is crucial to the survival of vertebrates
We identify a new population of blood vessel associated cells termed perivascular fibroblasts, which originate from the sclerotome, an embryonic structure that is previously known to generate the skeleton of the animal
Summary
Blood vessels must rapidly expand and contract in response to systemic cues, and be sturdy to withstand the stress of blood flow To maintain their integrity, blood vessels are supported by a highly specialized perivascular architecture comprised of blood vessel associated cells and the surrounding extracellular matrix (ECM) [1, 2]. The prevailing model is that vascular stability is maintained at three different levels: endothelial cells, mural cells and the surrounding ECM [2]. EDS patients are characterized by a significant vascular fragility that often leads to spontaneous rupture of blood vessel walls. Work in both animal models and human patients shows the importance of collagen in maintaining vascular stability. One unresolved question is how newly formed blood vessels are stabilized in the early time window before the differentiation of mural cells
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