VEGFA Isoforms as Pro-Angiogenic Therapeutics for Cerebrovascular Diseases

Abstract

Therapeutic angiogenesis has long been considered a viable treatment for vasculature disruptions, including cerebral vasculature diseases. One widely-discussed treatment method to increase angiogenesis is vascular endothelial growth factor (VEGF) A. In animal models, treatment with VEGFA proved beneficial, resulting in increased angiogenesis, increased neuronal density, and improved outcome. However, VEGFA administration in clinical trials has thus far failed to replicate the promising results seen in animal models. The lack of beneficial effects in humans and the difficulty in medicinal translation may be due in part to administration methods and VEGFA's ability to increase vascular permeability. One solution to mitigate the side effects of VEGFA may be found in the VEGFA isoforms. VEGFA is able to produce several different isoforms through alternative splicing. Each VEGFA isoform interacts differently with both the cellular components and the VEGF receptors. Because of the different biological effects elicited, VEGFA isoforms may hold promise as a tangible potential therapeutic for cerebrovascular diseases.

Keywords: VEGFA; angiogenic therapy; cerebral vasculature; isoforms.

Figure 1

VEGFA signaling in cerebrovascular diseases. Vascular endothelial growth factor A (VEGFA)-induced signaling in cerebrovascular disease can lead to both detrimental (red) and beneficial effects (green). BBB: blood–brain barrier. ROS: reactive oxygen species. CBF: cerebral blood flow.

Figure 2

Comparison of VEGFA to its isoforms. The eight exons of vascular endothelial growth factor A (VEGFA) have been arranged to highlight occurrences of alternative splicing in each isoform. VEGFR: vascular endothelial growth factor receptor. ECM: extracellular matrix. Nrp: neuropilin. Image created with BioRender.com.