VEGF165a and VEGF165b: Molecular effects of opposing isoforms in angiogenesis

Year 2025, Volume: 3 Issue: 3, 147 - 155, 29.10.2025

Funda Çimen Açıkgül , Seçil Nazife Parlak

https://doi.org/10.61845/agrimedical.1684066

Abstract

This review aims to comparatively examine the structural differences, receptor interactions, downstream signaling effects, and pathophysiological roles of the two main isoforms of the VEGFA gene, VEGF165a and VEGF165b, which arise from alternative splicing of exon 8. Recent experimental and clinical studies conducted between 2020 and 2025 in both human and animal models were systematically reviewed to evaluate the biological functions, receptor-binding properties, and pro- and anti-angiogenic effects of VEGF165b. VEGF165a promotes endothelial cell proliferation, migration, and vascular permeability by activating VEGFR-2 through PI3K/Akt and MAPK/ERK pathways. In contrast, VEGF165b binds to the same receptors but induces weak signaling and competitively inhibits the effects of VEGF165a. While VEGF165b is predominantly expressed in healthy tissues, a shift in favor of VEGF165a is observed in pathological conditions such as cancer, proliferative diabetic retinopathy, and age-related macular degeneration. Conversely, excessive VEGF165b expression is associated with impaired angiogenesis in diseases such as peripheral artery disease, systemic sclerosis, and preeclampsia. Disruption in the VEGF165 isoform balance underlies many diseases characterized by either excessive or insufficient angiogenesis. In this context, isoform-specific therapeutic strategies—such as the modulation of alternative exon usage via splice-switching oligonucleotides—may allow the development of more precise and targeted vascular therapies in the future. The VEGF165a/VEGF165b ratio also holds promise as a biomarker for guiding personalized angiogenesis-modulating treatments.

Keywords

Angiogenesis , Alternative splicing , isoforms , Vascular endothelial growth factor A , VEGFR-2 receptor , Signal transduction

Ethical Statement

This article is a literature-based review and does not involve human participants or animal experiments; therefore, ethical approval was not required.

VEGF165a ve VEGF165b: Anjiyogenezde zıt izoformların moleküler etkileri

Abstract

Bu derleme, VEGFA geninin alternatif ekzon 8 bölgesinden türeyen iki ana izoformu olan VEGF165a ve VEGF165b’nin yapısal farklılıklarını, reseptör etkileşimlerini, sinyal yolakları üzerindeki etkilerini ve bu izoformların hastalıklardaki patofizyolojik rollerini karşılaştırmalı olarak incelemeyi amaçlamaktadır. İnsan ve hayvan modellerinde yapılan deneysel ve klinik çalışmalara ait 2020–2025 yılları arasındaki güncel literatür taranmış, VEGF165b’nin biyolojik işlevleri, reseptör bağlanma özellikleri, pro- ve anti-anjiyogenik etkileri ile ilgili bulgular sistematik olarak derlenmiştir. VEGF165a, VEGFR-2 üzerinden PI3K/Akt ve MAPK/ERK yolaklarını aktive ederek endotel hücre proliferasyonu, göçü ve damar geçirgenliğini artırırken; VEGF165b bu reseptörlere bağlanmasına rağmen sinyallemeyi zayıf biçimde tetiklemekte ve VEGF165a’nın etkilerini kompetitif olarak baskılamaktadır. VEGF165b ekspresyonu sağlıklı dokularda baskın iken, kanser, proliferatif diyabetik retinopati ve yaşa bağlı makula dejenerasyonu gibi hastalıklarda VEGF165a lehine bir dengesizlik gözlenmektedir. Öte yandan, periferik arter hastalığı, sistemik skleroz ve preeklampsi gibi durumlarda VEGF165b’nin aşırı ekspresyonu yetersiz anjiyogenez ile ilişkilidir. VEGF165 izoform dengesindeki bozulmalar, anjiyogenez fazlalığı ya da yetersizliği ile seyreden birçok hastalığın temelinde yer almaktadır. Bu bağlamda, izoformlara özgü tedavi yaklaşımları (örneğin splice-switching oligonükleotidlerle alternatif ekson kullanımının yönlendirilmesi) gelecekte daha hassas ve hedefe yönelik damar tedavileri geliştirilmesine olanak sağlayabilir. VEGF165a/VEGF165b oranının biyobelirteç olarak kullanımı, kişiye özel anjiyogenez modülasyonuna yönelik önemli bir potansiyel taşımaktadır.

Keywords

Anjiyogenez , Alternatif dizi birleştirme , İzoformlar , Vasküler endotelyal büyüme faktörü A , VEGFR-2 reseptörü , Sinyal iletimi

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