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Related Experiment Video

Updated: Jun 24, 2026

Using the E1A Minigene Tool to Study mRNA Splicing Changes

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Published on: April 22, 2021

Microenvironment changes (in pH) affect VEGF alternative splicing.

Ana Paula Elias¹, Sergio Dias

¹Angiogenesis Laboratory, Centro de Investigação em Patobiologia Molecular (CIPM), Instituto Português de Oncologia de Francisco Gentil, Lisboa, Portugal.

Cancer Microenvironment : Official Journal of the International Cancer Microenvironment Society

|March 25, 2009

Summary

Acidosis, or low pH, significantly alters vascular endothelial growth factor-A (VEGF-A) splicing, increasing VEGF121 production. This process involves the p38 stress pathway and specific splicing factors.

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Area of Science:

Molecular Biology
Cell Biology
Cancer Research

Background:

Vascular endothelial growth factor-A (VEGF-A) exists in multiple isoforms with distinct functions.
Alternative splicing of VEGF-A is critical for its role in tumor angiogenesis.
Mechanisms regulating VEGF-A alternative splicing are not fully understood.

Purpose of the Study:

To investigate microenvironment cues that regulate VEGF-A alternative splicing.
To determine the effect of varying pH on VEGF-A isoform production.

Main Methods:

Endometrial cancer cells producing all VEGF isoforms were used as a model.
Cells were exposed to different pH levels, hormones, glucose, and CoCl(2) (hypoxia mimic).
VEGF splicing patterns, p38 pathway activation, and SR protein expression/phosphorylation were analyzed. siRNA was used to down-regulate specific SR proteins.

Main Results:

Low pH (acidosis) significantly increased VEGF121 isoform production compared to other isoforms (VEGF145, 165, 189).
Acidosis activated the p38 stress pathway and increased expression and phosphorylation of SR proteins (splicing factors).
Down-regulation of SR proteins SF2/ASF, SRp20, and SRp40 using siRNA blocked the pH-induced shift in VEGF isoforms.

Conclusions:

Acidosis is a novel regulator of VEGF-A alternative splicing.
The p38 stress pathway and specific SR proteins are likely involved in mediating the effects of low pH on VEGF-A splicing.
Findings provide new insights into the regulation of VEGF-A isoforms in the tumor microenvironment.