Vasculogenesis

In vasculogenesis, mesodermal cells differentiate to Vascular Progenitor Cells (VPCs) and endothelial cells (ECs) and form a vascular plexus. Maturation and stabilisation of the nascent plexus relies on the recruitment of pericute cells (PCs) and vascular smooth muscle cells (vSMCs) and deposition of extracellular matrix under the control of the coordinated action of PDGF, Ang2 (angiopoietin 2) and TGFβ signalling.

Studies in mice have underscored the essential role of VEGF-A and its receptors in vascular development:

  • Inactivation of Vegfa is embryonic lethal at E9.5-10.5 due to severe defects in vascular development.
  • Inactivation of the Vegfr1 is embryonic lethal at E8.5–9.0, due to increased VPC commitment and vascular disorganization owing to EC overgrowth
  • Knockout of Vegfr2 is embryonic lethal at E8.5–9.5, because of defective blood-island formation and vasculogenesis.

Despite the importance of VEGF-A in regulating vasculogenesis almost nothing is known about the downstream signals that mediate this effect. Though ECs, VPCs and mesodermal cells are different cells, the ECs are the differentiated derivative of the VPC, they all respond to VEGF-A. Our current knowledge of VEGF-A signaling is limited to differentiated ECs and angiogenesis.

In our lab we are interested in:

  • determining the VEGF-induced transcriptome and chromatin accessibility in VEGF-A-treated mesodermal progenitors by single cell RNAseq and single cell ATAC-seq, and

  • using beyond the state-of-the-art phosphoproteomics to pinpoint key phosphorylation events downstream of VEGF-A in the differentiation of mesodermal derivatives to VPCs and then ECs during vasculogenesis

  • evaluate the involvement of flow/shear stress and Mural cells in the differentiation of hiPSCs to ECs via mesodermal intermediates.