Reconciling VEGF With VPF: The Importance of Increased Vascular Permeability for Stroma Formation in Tumors, Healing Wounds, and Chronic Inflammation

Abstract

It is widely believed that vascular endothelial growth factor (VEGF) induces angiogenesis by its direct mitogenic and motogenic actions on vascular endothelial cells. However, these activities are only detected when endothelial cells are cultured at very low (0.1%) serum concentrations and would not be expected to take place at the much higher serum levels found in angiogenic sites in vivo. This conundrum can be resolved by recalling VEGF's original function, that of an extremely potent vascular permeability factor (VPF). In vivo VPF/VEGF increases microvascular permeability such that whole plasma leaks into the tissues where it undergoes clotting by tissue factor that is expressed on tumor and host connective tissue cells to deposit fibrin and generate serum. By providing tissue support and by reprogramming the gene expression patterns of cells locally, fibrin and serum can together account for the formation of vascular connective tissue stroma. In sum, by increasing vascular permeability, VPF/VEGF triggers the "wound healing response," setting in motion a fundamental pathophysiological process that induces the mature stroma that is found not only in healing wounds but also in solid tumors and chronic inflammatory diseases. Once initiated by increased vascular permeability, this response may be difficult to impede, perhaps contributing to the limited success of anti-VEGF therapies in treating cancer.

Keywords: VPF/VEGF; angiogenesis; chronic inflammation; delayed hypersensitivity; stroma; tumors; vascular permeability; wound healing.

FIGURE 1

Schematic diagram of stroma formation in tumors and wounds. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) initiates the wound healing response by increasing vascular permeability. As a result, whole plasma including plasma proteins extravasate by way of transcellular (VVO) and/or paracellular pathways. Tumor, connective tissue, and wound cells express tissue factor to trigger the extrinsic clotting system, generating serum, and depositing fibrin. Fibrin provides support for tumor cells and the ingrowth of new blood vessels and fibroblasts that synthesize collagen and other structural proteins. Fibrin degradation products are proangiogenic. Serum reprograms the gene expression patterns of tumor and host connective tissue cells. Over time, vascular connective tissue is replaced by dense fibrous connective tissue stroma termed scar in wounds and desmoplasia in tumors. Modified from Dvorak (2019, Figure 3) and Dvorak (b, Figure 1) with permissions.