VEGF165: The "Core Switch" of Angiogenesis and a Key Target in Disease Diagnosis and Treatment

Abstract

Vascular endothelial growth factor 165 (VEGF165), the predominant functional isoform of VEGF-A, serves as the "master regulator" of angiogenesis, playing a pivotal role in tissue development, repair, and the pathogenesis of numerous major diseases. This article comprehensively analyzes the unique molecular characteristics of VEGF165, delves into its dual roles in tumor growth, ophthalmic diseases, cardiovascular diseases, and wound healing, and systematically elaborates on the revolutionary therapeutic strategies targeting VEGF165 and their future prospects.

I. VEGF165: The "Core Engineer" of Vascular Construction

1. Molecular Characteristics: Why Is It the Key Isoform?

The VEGF-A gene generates multiple isoforms (e.g., VEGF121, VEGF165, VEGF189) through alternative splicing. VEGF165 is the most abundant and biologically versatile dominant isoform in the human body, attributed to its unique structure:

Full functional domain structure: It possesses both the receptor-binding domain that interacts with vascular endothelial growth factor receptors (VEGFRs) and the heparin-binding domain that binds to cell surface and extracellular matrix heparan sulfate proteoglycans.

Dynamic distribution properties: The heparin-binding domain allows VEGF165 to diffuse freely while being locally anchored, forming precise concentration gradients in tissues that act like "navigation signals" to guide the directional migration and growth of vascular endothelial cells.

Primary signal trigger: VEGF165 is the most effective ligand for activating its main receptor, VEGFR2 (the key switch for angiogenesis), initiating downstream signaling pathways such as MAPK and PI3K/Akt, which drive endothelial cell proliferation, migration, and survival.

2. Core Physiological Functions

Angiogenesis: Promotes the sprouting and growth of new blood vessels from existing ones, supplying oxygen and nutrients to tissues.

Vascular permeability: Rapidly increases microvascular permeability (formerly termed "vascular permeability factor"), facilitating plasma protein extravasation to provide a provisional matrix for vascular growth.

Cell survival: Acts as a survival factor for endothelial cells, inhibiting apoptosis.

II. The Profound Association of VEGF165 with Major Diseases

1. Cancer: The Tumor's "Lifeline" and Malignant Driver

VEGF165 is the primary culprit behind tumor growth and metastasis, forming the basis of the classic "angiogenic switch" theory.

Mechanism: Rapidly growing tumors create hypoxic microenvironments that induce tumor cells to secrete large amounts of VEGF165.

Consequences:

Feeding tumors: Stimulates the formation of abundant, tortuous, leaky, and dysfunctional neovasculature, providing nutrients to tumors.

Promoting metastasis: Abnormal blood vessels serve as conduits for cancer cells to enter the circulatory system, while increased vascular permeability facilitates extravasation.

Clinical significance: In the majority of solid tumors (e.g., lung, colorectal, and breast cancers), high VEGF165 expression is an independent predictor of poor prognosis, making it a prime target for anticancer therapy.

2. Ophthalmic Diseases: The Vision Killer

In the delicate organ of the eye, uncontrolled VEGF165 is the primary cause of irreversible vision loss.

Wet age-related macular degeneration (wAMD): Choroidal abnormal neovascularization, driven by VEGF165, leads to hemorrhage, exudation, and retinal detachment, resulting in rapid central vision decline.

Diabetic macular edema (DME): Hyperglycemia and hypoxia elevate retinal VEGF165 levels, disrupting the blood-retinal barrier and causing fluid leakage and macular edema, the leading cause of blindness in diabetic patients.

Retinal vein occlusion (RVO): Ischemic regions exhibit surging VEGF165 levels, leading to vascular leakage and neovascularization, which cause macular edema and vitreous hemorrhage.

3. Cardiovascular Diseases: A Dual Role in Ischemia and Repair

Harmful aspect: In atherosclerotic plaques, VEGF165 promotes intraplaque neovascularization. These fragile vessels are prone to rupture, potentially triggering plaque hemorrhage and instability, increasing the risk of myocardial infarction.

Beneficial aspect: In myocardial infarction or lower limb ischemia, localized delivery of VEGF165 (via gene or protein therapy) aims to promote therapeutic angiogenesis, establishing collateral circulation to salvage ischemic tissues—a key focus of regenerative medicine.

4. Other Diseases

Rheumatoid arthritis: In inflamed joints, VEGF165 promotes "pannus" formation, supplying nutrients to inflammatory cells and exacerbating joint destruction.

Preeclampsia: Dysregulated placental VEGF165 signaling is closely linked to maternal hypertension and proteinuria.

Chronic wounds: Insufficient local VEGF165 expression in conditions like diabetic foot ulcers impairs reparative angiogenesis, hindering wound healing.

III. Targeting VEGF165: A Success Story in Modern Medicine

Drugs targeting the VEGF165 pathway are among the most successful targeted therapies in oncology and ophthalmology.

1. Anticancer Drugs

Bevacizumab: A recombinant humanized anti-VEGF monoclonal antibody that neutralizes all VEGF-A isoforms (including VEGF165) like a "sponge." Combined with chemotherapy, it has become a standard treatment for various cancers.

VEGFR tyrosine kinase inhibitors: Such as sunitinib and pazopanib, which block the pathway by inhibiting intracellular VEGF signal transduction.

2. Ophthalmic Drugs (Intravitreal Injection)

Ranibizumab, aflibercept, and conbercept: Specifically target VEGF165 and other isoforms, inhibiting neovascularization and reducing leakage. These drugs are now first-line therapies for wAMD and DME, saving the vision of millions worldwide.

Bevacizumab: Used off-label as a low-cost alternative with proven efficacy.

3. Challenges and Future Directions

Drug resistance: Efficacy may decline with prolonged use.

Side effects: Such as hypertension and proteinuria (systemic use) or endophthalmitis (intraocular injection).

Next-generation strategies: Developing longer-lasting drugs, exploring therapies targeting specific isoforms (e.g., VEGF165b, an inhibitory splice variant), and combining anti-VEGF with immunotherapy, radiotherapy, etc.

IV. Conclusion and Outlook

VEGF165 is a critical "double-edged sword" in life processes. It is both a cornerstone of embryonic development and tissue repair and a powerful driver of devastating diseases like cancer and blindness. By developing "precision missiles" targeting VEGF165, humanity has achieved milestone victories in the battle against these diseases. In the future, with deeper insights into the VEGF signaling network (e.g., its roles in different cell types and interactions with other pathways) and advancements in precise delivery and modulation technologies (e.g., gene editing, tissue-specific nanomedicines), we can more safely suppress its pathogenic effects while better harnessing its regenerative potential, opening new therapeutic horizons for human health.