Notch in Pericytes: Receptor Function and Targets

Abstract

Angiogenesis is the process by which pre-existing blood vessels sprout to from new ones. Mural cell recruitment to the capillary endothelium is essential for the stabilization of a newly forming vascular bed during angiogenesis and is tightly regulated. Notch signaling is a pathway that regulates vessel function and pericyte recruitment. Pericyte dysfunction has been identified to play a role in diseases such as diabetic retinopathy, Alzheimer’s disease, amyotrophic lateral sclerosis, and arteriovenous malformations. Yet, the molecular control of pericyte function is not fully understood. Endothelial cell Notch signaling has been well characterized, while pericyte Notch signaling is less understood. It has been shown that Notch1 and Notch3 receptors are present in pericytes, yet the downstream control of either receptor of their targets is unclear. Here, we explored the function of pericyte Notch1 in vivo. We found that removal of Notch1 in pericytes did not affect angiogenesis, but it resulted arterial diameter increase in postnatal day (P) 14 mice. Increased arterial diameter was not present at 6 weeks old, suggesting that pericyte Notch1 is not a critical regulator of arterial diameter. We also examined downstream two target genes of Notch signaling in order to characterize their role in pericyte function: Matrix Metalloproteinase 14 (MMP14) and Plexin Domain Containing-1 (PLXDC1). MMP14 plays a role in vasculature remodeling, however its role in pericytes remains unknown. We found that vessel density of P14 mouse peripheral capillaries was significantly increased in mice lacking perivascular MMP14. Additionally, the diameter of arteries at the center of the retina was significantly decreased, suggesting that pericyte MMP14 plays a role in regulating angiogenesis and arterial diameter. We also performed in vitro studies to evaluate PLXDC1, a recently identified target of Notch signaling in pericytes. PLXDC1 removal from human brain vascular pericytes showed no changes in migration, viability or apoptosis; however, we observed significantly increased invasion through a three-dimensional matrix. These results suggest that PLXDC1 plays a role in pericyte invasion.