Tumor Blood Vessel Dynamics During and After Angiogenesis Inhibition

Abstract

Inhibitors of VEGF signaling cause robust and rapid changes in blood vessels of tumors. The inhibitors block angiogenesis, have potent antivascular actions resulting in regression of tumor vessels, and reduce the abnormality of tumor vessels that survive. Within hours, endothelial fenestrations and vascular sprouts disappear, and patency is lost and blood flow ceases in a population of tumor vessels. By the end of the first week, as many as 80% of tumor vessels regress. Surviving tumor vessels acquire more normal structural and functional features, in a process called normalization. Pericytes of tumor vessels are not as severely impacted by VEGF inhibitors as endothelial cells. Empty sleeves of vascular basement membrane persist after tumor vessels regress, providing a historical record of degenerated tumor vessels and a scaffold for vascular regrowth. Withdrawal of treatment leads to regrowth of endothelial sprouts into empty sleeves of basement membrane. Regrowth begins within a day after withdrawal of inhibitors that are rapidly cleared. Within a week, tumors may be fully revascularized with functional blood vessels. These results raise the possibility that empty sleeves of vascular basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti‐VEGF therapy and highlight their importance as potential targets in cancer therapy.