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Target: VEGFA


Research on the Target VEGFA

1. Target Summary:

Vascular Endothelial Growth Factor A (VEGFA) is a key signaling protein that plays a crucial role in angiogenesis, the process of new blood vessel formation. It is primarily involved in physiological processes such as wound healing and embryonic development, but it also contributes to pathological conditions, including cancer and neurodegenerative diseases. VEGFA is a major therapeutic target due to its involvement in tumor growth and metastasis, making it a focal point in the development of anti-angiogenic therapies.

2. Mechanism:

VEGFA exerts its effects through binding to its receptors, primarily VEGFR-1 and VEGFR-2, which are expressed on endothelial cells. This binding activates several downstream signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt pathway and the mitogen-activated protein kinase (MAPK) pathway, leading to endothelial cell proliferation, migration, and survival.
  • Angiogenesis: VEGFA promotes the formation of new blood vessels by stimulating endothelial cell proliferation and migration. It also increases vascular permeability, allowing for the delivery of nutrients and oxygen to tissues.
  • Tumor Microenvironment: In cancer, VEGFA is secreted by tumor cells and surrounding stromal cells, creating a pro-angiogenic environment that supports tumor growth and metastasis. Elevated levels of VEGFA are often associated with poor prognosis in various cancers, including colorectal cancer (Canavese et al., 2017; PMID: 27943279).
  • Neuroprotection and BBB Integrity: In neurodegenerative diseases, VEGFA has a dual role. While it can promote neuroprotection and enhance blood-brain barrier (BBB) integrity, excessive VEGFA can lead to increased permeability and contribute to neurodegeneration (Lange et al., 2016; PMID: 27364743).

3. Approved Drugs:

Several anti-VEGF therapies have been developed and approved for clinical use, including:
  • Bevacizumab (Avastin): A monoclonal antibody that binds to VEGFA, preventing it from interacting with its receptors.
  • Aflibercept (Zaltrap): A fusion protein that acts as a decoy receptor for VEGFA and placental growth factor (PlGF).
  • Ranibizumab (Lucentis): A monoclonal antibody fragment that inhibits VEGFA and is used primarily in ophthalmology for conditions like age-related macular degeneration (AMD).

4. Hypotheses:

  • VEGFA as a Biomarker: It is hypothesized that VEGFA levels can serve as a predictive biomarker for the efficacy of anti-VEGF therapies. Elevated VEGFA may correlate with tumor aggressiveness and treatment resistance (Gyanchandani & Kim, 2013; PMID: 23386694).
  • Role in Neurodegeneration: Another hypothesis posits that dysregulation of VEGFA signaling contributes to the pathogenesis of neurodegenerative diseases by impairing BBB integrity and promoting neuroinflammation (Tsartsalis et al., 2024; PMID: 38472200).

5. Validation:

  • Clinical Evidence: Numerous studies have validated the role of VEGFA in cancer progression and treatment response. For instance, specific VEGFA isoforms have been linked to poor prognosis in colorectal cancer (Canavese et al., 2017; PMID: 27943279).
  • Biomarker Studies: Research has identified biomarkers in the aqueous humor of patients with neovascular AMD that correlate with treatment response to anti-VEGF therapy, such as apolipoprotein-B100 (Cao et al., 2022; PMID: 34874918).

6. Clinical Trials:

Clinical trials have extensively evaluated the efficacy of anti-VEGF therapies in various cancers and ocular diseases. For example, the YOSEMITE and RHINE trials assessed the efficacy of faricimab, a bispecific antibody targeting both VEGFA and angiopoietin-2, in patients with diabetic macular edema (Eter et al., 2022; PMID: 36246184).

7. Involved Pathways:

VEGFA is involved in several key signaling pathways:
  • PI3K/Akt Pathway: Promotes cell survival and proliferation.
  • MAPK Pathway: Regulates cell growth and differentiation.
  • HIF-1 Pathway: Involved in the cellular response to hypoxia, enhancing VEGFA expression under low oxygen conditions (Shi et al., 2025; PMID: 40049050).

8. Associated Genes:

  • VEGFA: The primary gene encoding the VEGFA protein.
  • VEGFR1 and VEGFR2: Receptors that mediate the effects of VEGFA.
  • HIF1A: A transcription factor that regulates VEGFA expression in response to hypoxia (Tsartsalis et al., 2024; PMID: 38472200).

9. Target Expression:

VEGFA is expressed in various tissues, with particularly high levels in tumors and during pathological conditions such as inflammation and ischemia. Its expression can be influenced by factors such as hypoxia and inflammatory cytokines.

10. Additional Context:

VEGFA's role extends beyond angiogenesis; it is also implicated in processes such as inflammation, wound healing, and neuroprotection. Understanding its multifaceted roles can aid in developing targeted therapies that modulate its activity for therapeutic benefit.

11. References:

  1. Canavese M, Ngo DT, Maddern GJ. Biology and therapeutic implications of VEGF-A splice isoforms and single-nucleotide polymorphisms in colorectal cancer. Int J Cancer. 2017; 27943279.
  2. Shi Z, Kuai M, Li B. The role of VEGF in Cancer angiogenesis and tumorigenesis: Insights for anti-VEGF therapy. Cytokine. 2025; 40049050.
  3. Lange C, Storkebaum E, de Almodovar CR. Vascular endothelial growth factor: a neurovascular target in neurological diseases. Nat Rev Neurol. 2016; 27364743.
  4. Cao X, Sanchez JC, Dinabandhu A. Aqueous proteins help predict the response of patients with neovascular age-related macular degeneration to anti-VEGF therapy. J Clin Invest. 2022; 34874918.
  5. Gyanchandani R, Kim S. Predictive biomarkers to anti-VEGF therapy: progress toward an elusive goal. Clin Cancer Res. 2013; 23386694.
This comprehensive overview of VEGFA highlights its critical role in both cancer and neurodegenerative diseases, emphasizing the need for continued research to optimize therapeutic strategies targeting this important growth factor.