Adult-induced genetic ablation distinguishes PDGFB roles in blood-brain barrier maintenance and development

Abstract

Platelet-derived growth factor B (PDGFB) released from endothelial cells is indispensable for pericyte recruitment during angiogenesis in embryonic and postnatal organ growth. Constitutive genetic loss-of-function of PDGFB leads to pericyte hypoplasia and the formation of a sparse, dilated and venous-shifted brain microvasculature with dysfunctional blood-brain barrier (BBB) in mice, as well as the formation of microvascular calcification in both mice and humans. Endothelial PDGFB is also expressed in the adult quiescent microvasculature, but here its importance is unknown. We show that deletion of Pdgfb in endothelial cells in 2-months-old mice causes a slowly progressing pericyte loss leading, at 12–18 months of age, to ≈50% decrease in endothelial:pericyte cell ratio, ≈60% decrease in pericyte longitudinal capillary coverage and >70% decrease in pericyte marker expression. Similar to constitutive loss of Pdgfb, this correlates with increased BBB permeability. However, in contrast to the constitutive loss of Pdgfb, adult-induced loss does not lead to vessel dilation, impaired arterio-venous zonation or the formation of microvascular calcifications. We conclude that PDFGB expression in quiescent adult microvascular brain endothelium is critical for the maintenance of pericyte coverage and normal BBB function, but that microvessel dilation, rarefaction, arterio-venous skewing and calcification reflect developmental roles of PDGFB.

In vivo Single Cell Optical Ablation of Brain Pericytes

“…However, congenital pericyte deficiency may not accurately represent the loss of pericytes that occurs with aging, or injury and disease in the adult brain. To this end, the extensive dilation of microvessels and reduction in capillary density that occurs with congenital pericyte loss is not observed in mouse models of adult onset pericyte loss (Vazquez-Liebanas et al, 2022).…”

“…Pericytes are embedded in the vascular basement membrane, forming peg-and-socket connections with endothelial cells (Ornelas et al, 2021). This close apposition allows pericytes to serve many essential roles, including formation and maturation of blood vessels (Gerhardt and Betsholtz, 2003;von Tell et al, 2006), integrity of the blood-brain barrier (BBB) (Armulik et al, 2010;Daneman et al, 2010;Vazquez-Liebanas et al, 2022), and control of capillary tone and blood flow (Hall et al, 2014;Kisler et al, 2017;Berthiaume et al, 2018;Hartmann et al, 2021).…”

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

“…PDGF-B/PDGFRb signaling is involved in pericyte coverage during adulthood since genetic ablation of endothelial PDGF-BB in adult mice leads to age-dependent pericyte loss and BBB defects. 22 Augmenting PDGF-B/PDGFRb activity in adulthood may therefore be a strategy to increase pericyte coverage and improve capillary homeostasis. In vitro, administration of PDGF-BB leads to proliferation of human brain pericytes and protection from apoptosis.…”

Identification, discrimination and heterogeneity of fibroblasts

“…VSMCs contain a contractile machinery involving several proteins, among them alpha-smooth muscle actin ( ASMA , Acta2) , which is a highly expressed and often-used smooth muscle cell marker. Pericytes probably have multiple and organ-specific functions, for example in the brain where they are essential for the maturation and maintenance of the blood-brain barrier 82 , 83 . Molecularly, pericytes can be distinguished from VSMCs by for example abundant expression of potassium inwardly rectifying channel subfamily J member 8 ( Kcnj8 ) and absent or very low (relative to VSMCs) expression of transcripts encoding the smooth muscle contractile machinery 60 .…”