Polysialic acid regulates glomerular microvasculature formation by interaction with VEGF-A188 in mice

Abstract

Vascular endothelial growth factor A (VEGF-A) is a key signalling protein that stimulates blood vessel development and repair. Its tight control is essential for organ development and tissue homeostasis. However, the complex regulatory network for balanced bioavailability of VEGF-A is not fully understood. Here, we assessed the role of the glycocalyx component polysialic acid (polySia) for kidney development and its potential interactions with VEGF-A isoforms, in vitro and in vivo, using mouse models of polySia deficiency. PolySia acts as negative regulator of cell adhesion, but also may interact with extracellular components. In murine kidney, polySia was identified on nephron progenitor and endothelial cell subsets in developing nephrons with declining expression during maturation. Loss of polySia in Ncam^−/− mice revealed the neural cell adhesion molecule NCAM as major protein carrier. Both polysialyltransferase-negative and Ncam^−/− mice displayed impaired glomerular microvasculature development with reduced endothelial cell numbers, reminiscent to the phenotype of mice with impaired VEGF-A signalling. In vitro, immobilized polySia specifically interacted with the VEGF-A188 isoform demonstrating an isoform-specific direct interaction. Single cell RNA sequencing data analysis of newborn mouse kidneys implicated activation of VEGF-A-signalling in polysialyltransferase-positive endothelial cells. Consistently, loss of polySia resulted in diminished VEGFR2 activation in perinatal kidney and human endothelial cells. At transcriptional level, the expression of polysialyltransferases and known polySia carrier proteins is conserved in human developing kidney. Together, these data demonstrate a direct impact of polySia on VEGF-A signalling with the perspective that polysialylation could be a therapeutic target to ameliorate microvasculature repair after renal injury.

Graphical abstract