Venousization Enables Vascular Growth Independent of VEGF Receptor Signaling

We found that Vegfr2KO ECs are not able to sprout during the first wave of angiogenesis in most tissues, because it is highly VEGF-dependent and favours the growth and mobilization of wild-type ECs. However, due to their inability to respond to VEGF, over time Vegfr2KO ECs become dominant in veins, which provide for a long term and continuous source of ECs for subsequent waves of VEGF-independent angiogenesis. Comparative scRNAseq analysis of ECs with acute and long-term loss of VEGFR2, revealed both common and organ-specific molecular mechanisms of adaptation and resistance to VEGF signalling loss.

This included significant endothelial venousization and the upregulation of ligands for VEGFR1 and VEGFR3. VEGFR1 only partially compensated for VEGFR2 loss in capillary ECs, whereas VEGFR3 only compensated in arterial ECs. Loss of the three VEGF receptors did not compromise venous growth.

Importantly, loss of the master regulator of venous development NR2F2/COUP-TFII, significantly compromised the expansion of Vegfr2KO ECs. This work changes our understanding of the role of VEGF receptors in angiogenesis and reveals venousization as a mechanism of adaptation and resistance to VEGF signalling loss.