Abstract
Pericytes adhere to the abluminal surface of endothelial tubules and are required for the formation of stable vascular networks. Defective endothelial cell-pericyte interactions are frequently observed in diseases characterized by compromised vascular integrity such as diabetic retinopathy. Many functional properties of pericytes and their exact role in the regulation of angiogenic blood vessel growth remain elusive. Here we show that pericytes promote endothelial sprouting in the postnatal retinal vasculature. Using genetic and pharmacological approaches, we show that the expression of vascular endothelial growth factor receptor 1 (VEGFR1) by pericytes spatially restricts VEGF signalling. Angiogenic defects caused by pericyte depletion are phenocopied by intraocular injection of VEGF-A or pericyte-specific inactivation of the murine gene encoding VEGFR1. Our findings establish that pericytes promote endothelial sprouting, which results in the loss of side branches and the enlargement of vessels when pericyte function is impaired or lost.
Highlights
Pericytes adhere to the abluminal surface of endothelial tubules and are required for the formation of stable vascular networks
This approach made use of Pdgfrb-CreERT2 transgenic mice, which express tamoxifen-inducible Cre recombinase (CreERT2) in PDGFRβ-expressing cells and preferentially in pericytes and vascular smooth muscle cells (vSMCs) of various organs[4, 33]. Acute ablation of these mural cells via CreERT2-controlled diphtheria toxin (DTA) or diphtheria toxin receptor (DTR) expression led to impaired endothelial sprouting and vascular patterning similar to defects seen after intraocular vascular endothelial growth factor A (VEGF-A) injection or Pdgfrb-CreERT2-mediated inactivation of the murine Flt[1] gene
As the VEGF-A/VEGFR2 signalling pathway is an important regulator of endothelial cells (ECs) sprouting and proliferation, we investigated whether diphtheria toxin/DTR-mediated pericyte ablation might lead to changes in this pathway
Summary
Pericytes adhere to the abluminal surface of endothelial tubules and are required for the formation of stable vascular networks. Pdgfb or Pdgfrb loss of-function embryos show vascular hyperplasia, microvessel dilation, and upregulation of vascular endothelial growth factor A (VEGF-A) expression[19] The latter binds and activates the receptor tyrosine kinase VEGFR2 on ECs, which triggers vascular growth and EC proliferation, increases vascular permeability[20, 21] and may explain edema formation in late gestation Pdgfb/Pdgfrb knockout embryos[19]. This approach made use of Pdgfrb-CreERT2 transgenic mice, which express tamoxifen-inducible Cre recombinase (CreERT2) in PDGFRβ-expressing cells and preferentially in pericytes and vSMCs of various organs[4, 33] Acute ablation of these mural cells via CreERT2-controlled diphtheria toxin (DTA) or diphtheria toxin receptor (DTR) expression led to impaired endothelial sprouting and vascular patterning similar to defects seen after intraocular VEGF-A injection or Pdgfrb-CreERT2-mediated inactivation of the murine Flt[1] gene. The sum of our data identifies pericytes as important regulators of VEGF signalling and thereby vascular patterning
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