Perivascular neurons instruct 3D vascular lattice formation via neurovascular contact

Cell. 2024 May 23;187(11):2767-2784.e23. doi: 10.1016/j.cell.2024.04.010. Epub 2024 May 10.


The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain.

Keywords: Piezo2; ischemic optic neuropathy; perivascular neurons; retinal ganglion cells; three-dimensional vascular architecture; vascular lattice formation; vascular perfusions.

MeSH terms

  • Animals
  • Cerebellum* / blood supply
  • Cerebellum* / cytology
  • Cerebellum* / metabolism
  • Female
  • Ion Channels / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neurons* / metabolism
  • Retina* / cytology
  • Retina* / metabolism
  • Retinal Ganglion Cells / metabolism
  • Retinal Vessels / metabolism


  • Ion Channels
  • Piezo2 protein, mouse