Early Actions of Anti–Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor Drugs on Angiogenic Blood Vessels

• Published in: The American journal of pathology Vol. 187; no. 10; pp. 2337 - 2347
• Main Authors: Sitohy, Basel, Chang, Sunghee, Sciuto, Tracey E., Masse, Elizabeth, Shen, Mei, Kang, Peter M., Jaminet, Shou-Ching, Benjamin, Laura E., Bhatt, Rupal S., Dvorak, Ann M., Nagy, Janice A., Dvorak, Harold F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2017; American Society for Investigative Pathology
• Subjects: Adenoviridae - metabolism; Angiogenesis Inhibitors - pharmacology; Animals; Bibenzyls - pharmacology; Blood Vessels - drug effects; Cell Death - drug effects; Cell Proliferation - drug effects; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Hypertension - pathology; Mice, Inbred C57BL; Mice, Nude; Microvessels - drug effects; Microvessels - pathology; Models, Biological; Neovascularization, Physiologic - drug effects; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide Synthase Type III - metabolism; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins - pharmacology; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2017.06.010

Tumors induce their heterogeneous vasculature by secreting vascular endothelial growth factor (VEGF)-A. Anti-VEGF/VEGF receptor (VEGFR) drugs treat cancer, but the underlying mechanisms remain unclear. An adenovirus expressing VEGF-A (Ad-VEGF-A164) replicates the tumor vasculature in mice without tumor cells. Mother vessels (MV) are the first angiogenic vessel type to form in tumors and after Ad-VEGF-A164. Multiday treatments with a VEGF trap reverted MV back to normal microvessels. We now show that, within hours, a single dose of several anti-VEGF drugs collapsed MV to form glomeruloid microvascular proliferations (GMP), accompanied by only modest endothelial cell death. GMP, common in many human cancers but of uncertain origin, served as an intermediary step in MV reversion to normal microvessels. The vasodisruptive drug combretastatin CA4 also targeted MV selectively but acted differently, extensively killing MV endothelium. Antivascular changes were quantified with a novel Evans blue dye assay that measured vascular volumes. As in tumors, Ad-VEGF-A164 strikingly increased endothelial nitric oxide synthase (eNOS) expression. The eNOS inhibitor N(G)-Nitro-l-arginine methyl ester mimicked anti-VEGF/VEGFR drugs, rapidly collapsing MV to GMP. Inhibition of eNOS reduces synthesis of its vasodilatory product, nitric oxide, leading to arterial contraction. Patients and mice receiving anti-VEGF/VEGFR drugs develop hypertension, reflecting systemic arterial contraction. Together, anti-VEGF/VEGFR drugs act in part by inhibiting eNOS, causing vasocontraction, MV collapse to GMP, and subsequent reversion of GMP to normal microvessels, all without extensive vascular killing.