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

Abstract

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-A) 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-A. 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-A 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.

Tumors: Wounds That Do Not Heal—A Historical Perspective with a Focus on the Fundamental Roles of Increased Vascular Permeability and Clotting

“…120 Collapsed MV form GMP, structures that mimic the glomeruli of normal kidneys (hence the name). 109,120,121 GMP are found in many human cancers and are particularly abundant in glioblastoma multiforme. 122,123 Over time, GMP devolve into normal appearing capillaries and venules, thus completing a cycle that begins with VEGF-Ainduced formation of MV from previously normal capillaries and venules; upon VEGF-A decline or inhibition, MV regress to structurally normal microvessels by way of GMP (►Fig.…”

“…4). 120,121,124 The mechanisms responsible for GMP devolution to normal microvessels upon VEGF-A withdrawal have not been worked out.…”

Morphological Characteristics and Clinical Significance of Different Types of Tumor Vessels in Patients with Stages I-IIA of Squamous Cervical Cancer

“…It should be noted that in the research mentioned above, the study of the prognostic significance of angiogenesis in cervical cancer was associated exclusively with a quantitative assessment of the expression of the various markers. Meanwhile, many modern studies indicate that vessels in tumors are heterogeneous and differ in origin, morphology, the degree of maturity, and sensitivity to anticancer therapy [ 57 – 60 ]. Thus, we previously studied the morphological features and clinical significance of different types of tumor vessels in gastric and breast cancer [ 31 , 32 ].…”

Inducing Angiogenesis, A Key Step in Cancer Vascularization, and Treatment Approaches

“…VEGF inhibition, by anti-VEGF/VEGF receptor, is shown to restore vasculature within hours to normal microvessels by way of GMP [73]. GMP is believed to act as an intermediary step in MV reversion to normal microvessels after VEGF blockade [74]. pharmacokinetic properties [75].…”