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Adult-induced genetic ablation distinguishes PDGFB roles in blood-brain barrier maintenance and development
Elisa Vazquez-Liebanas1, Khayrun Nahar1, Giacomo Bertuzzi1
1Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Insights
Platelet-derived growth factor B (PDGFB) in adult brain endothelial cells maintains pericyte coverage and blood-brain barrier function. Loss of PDGFB in adults impairs these functions but avoids developmental defects seen in constitutive loss.
Area of Science:
- Neuroscience
- Vascular Biology
- Cell Biology
Background:
- Platelet-derived growth factor B (PDGFB) is crucial for pericyte recruitment in developing blood vessels.
- Constitutive loss of PDGFB causes brain microvascular defects, including pericyte loss, BBB dysfunction, and calcification.
- The role of PDGFB in adult quiescent microvasculature remains unclear.
Purpose of the Study:
- To investigate the function of endothelial PDGFB in adult mice.
- To determine if adult-onset PDGFB deficiency impacts pericyte coverage, BBB integrity, and microvascular structure.
Main Methods:
- Conditional deletion of the *Pdgfb* gene in endothelial cells of adult mice.
- Longitudinal assessment of pericyte coverage, endothelial:pericyte ratio, and pericyte marker expression.
- Evaluation of blood-brain barrier permeability and microvascular morphology.
Main Results:
- Adult endothelial *Pdgfb* deletion led to progressive pericyte loss and reduced capillary coverage over 10-16 months.
- Increased blood-brain barrier permeability was observed in adult-induced PDGFB-deficient mice.
- Unlike constitutive loss, adult-induced loss did not cause vessel dilation, altered arterio-venous zonation, or microvascular calcification.
Conclusions:
- Endothelial PDGFB is essential for maintaining adult brain pericyte coverage and blood-brain barrier function.
- Microvascular dilation, rarefaction, arterio-venous skewing, and calcification are likely specific to developmental roles of PDGFB.
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.
