An intimate interplay between precocious, migrating pericytes and endothelial cells governs human fetal brain angiogenesis
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In order to better understand the process of angiogenesis in the developing human brain, we have examined the spatial relationship and relative contributions of endothelial cells and pericytes, the two primary cell types involved in vessel growth, together with their relation with the vascular basement membrane. Pericytes were immunolocalized through use of the specific markers nerve/glial antigen 2 (NG2) proteoglycan, endosialin (CD248) and the platelet-derived growth factor receptor β (PDGFR-β), while endothelial cells were identified by the pan-endothelial marker CD31 and the blood brain barrier (BBB)-specific markers claudin-5 and glucose transporter isoform 1 (GLUT-1). The quantitative analysis demonstrates that microvessels of the fetal human telencephalon are characterized by a continuous layer of activated/angiogenic NG2 pericytes, which tightly invest endothelial cells and participate in the earliest stages of vessel growth. Immunolabelling with anti-active matrix metalloproteinase-2 (aMMP-2) and anti-collagen type IV antibodies revealed that aMMP-2 producing endothelial cells and pericytes are both associated with the vascular basement membrane during vessel sprouting. Detailed localization of the two vascular cell types during angiogenesis suggests that growing microvessels of the human telencephalon are formed by a pericyte-driven angiogenic process in which the endothelial cells are preceded and guided by migrating pericytes during organization of the growing vessel wall.
KeywordsAngiogenesis Basement membrane Endosialin Endothelial cells Human brain MMP-2 NG2 PDGFR-β Pericytes
Active matrix metalloproteinase-2
Central nervous system
Glucose transporter isoform 1
Nerve/glial antigen 2
Platelet-derived growth factor receptor β
Vascular endothelial growth factor
This work was funded by Ministero dell’Istruzione Università e Ricerca (MIUR; FIRB 2001) and Fondazione Cassa di Risparmio di Puglia (FCRP 2005) to DV. We thank Clare M. Isacke and John R. MacFayden, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, for the generous gift of endosialin antibody. We gratefully acknowledge Mary V. C. Pragnell, BA for linguistic help, and Marisa Ambrosi, Antonella Grano, and Loredana Lorusso for their excellent technical assistance.
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