Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant...

Area of Science:

• Vascular biology
• Regenerative medicine
• Biotechnology

Background:

• Long-term vascular endothelial growth factor (VEGF) delivery for therapeutic angiogenesis can lead to abnormal blood vessel formation and hemangiomas.
• The relationship between VEGF dosage and the resulting vascular morphology and function requires further elucidation.

Purpose of the Study:

• To investigate the impact of VEGF dosage on the development of normal versus aberrant blood vessels.
• To determine the threshold of VEGF concentration critical for distinguishing between normal and abnormal angiogenesis.

Main Methods:

• Implantation of retrovirally transduced myoblasts expressing different levels of VEGF164 into adult mouse muscles.
• Analysis of vascular morphology, function, and stability in response to varying VEGF microenvironmental concentrations.
• Assessment of VEGF independence using VEGF-TrapR1R2 treatment.

Main Results:

• Reducing the overall number of VEGF-expressing cells did not prevent vascular abnormalities.
• A critical threshold of VEGF microenvironmental concentration was identified.
• Low to medium VEGF levels induced stable, pericyte-coated capillaries that were VEGF-independent.
• High VEGF levels resulted in hemangioma formation.
• Mixing cell populations showed that even a small proportion of high VEGF producers could induce hemangiomas.

Conclusions:

• The microenvironmental concentration of VEGF, not the overall dose, is the primary determinant of normal versus aberrant angiogenesis.
• Sustained VEGF delivery below a specific microenvironmental threshold can promote normal angiogenesis without other growth factors.
• This finding has significant implications for optimizing VEGF-based therapies for angiogenesis.