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Updated: May 21, 2026
A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Cardiovascular and systemic microvascular effects of anti-vascular endothelial growth factor therapy for cancer
J Todd Belcik1, Yue Qi, Beat A Kaufmann
1Division of Cardiovascular Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA.
Objectives:
This study sought to evaluate the contribution of microvascular functional rarefaction and changes in vascular mechanical properties to the development of hypertension and secondary ventricular remodeling that occurs with anti-vascular endothelial growth factor (VEGF) therapy.
Background:
Hypertension is a common side effect of VEGF inhibitors used in cancer medicine.
Methods:
Mice were treated for 5 weeks with an anti-murine VEGF-A monoclonal antibody, antibody plus ramipril, or sham treatment. Microvascular blood flow (MBF) and blood volume (MBV) were quantified by contrast-enhanced ultrasound in skeletal muscle, left ventricle (LV), and kidney. Echocardiography and invasive hemodynamics were used to assess ventricular function, dimensions and vascular mechanical properties.
Results:
Ambulatory blood pressure increased gradually over the first 3 weeks of anti-VEGF therapy. Compared with controls, anti-VEGF-treated mice had similar aortic elastic modulus and histological appearance, but a marked increase in arterial elastance, indicating increased afterload, and elevated plasma angiotensin II. Increased afterload in treated mice led to concentric LV remodeling and reduced stroke volume without impaired LV contractility determined by LV peak change in pressure over time (dp/dt) and the end-systolic dimension-pressure relation. Anti-VEGF therapy did not alter MBF or MBV in skeletal muscle, myocardium, or kidney; but did produce cortical mesangial glomerulosclerosis. Ramipril therapy almost entirely prevented the adverse hemodynamic effects, increased afterload, and LV remodeling in anti-VEGF-treated mice.
Conclusions:
Neither reduced functional microvascular density nor major alterations in arterial mechanical properties are primary causes of hypertension during anti-VEGF therapy. Inhibition of VEGF leads to an afterload mismatch state, increased angiotensin II, and LV remodeling, which are all ameliorated by angiotensin-converting enzyme inhibition.
Insights
Anti-vascular endothelial growth factor (VEGF) therapy causes hypertension by increasing afterload and angiotensin II, not microvascular changes. Angiotensin-converting enzyme inhibition prevents these adverse effects and ventricular remodeling.
Area of Science:
- Cardiovascular research
- Oncology
- Nephrology
Background:
- Hypertension is a frequent adverse effect of anti-VEGF therapies used in cancer treatment.
- VEGF inhibitors can lead to secondary ventricular remodeling.
Purpose of the Study:
- To investigate if microvascular rarefaction or altered vascular mechanics cause hypertension with anti-VEGF therapy.
- To determine the mechanisms of ventricular remodeling during anti-VEGF treatment.
Main Methods:
- Mice received anti-VEGF-A antibody, antibody plus ramipril, or sham treatment for 5 weeks.
- Microvascular blood flow and volume were measured using contrast-enhanced ultrasound.
- Echocardiography and invasive hemodynamics assessed cardiac function and vascular properties.
Main Results:
- Anti-VEGF therapy increased blood pressure, arterial elastance (afterload), and angiotensin II levels.
- Increased afterload induced concentric left ventricular (LV) remodeling and reduced stroke volume.
- Microvascular function and aortic mechanical properties remained unchanged; kidney damage occurred.
Conclusions:
- Hypertension from anti-VEGF therapy is due to increased afterload and angiotensin II, not microvascular rarefaction.
- VEGF inhibition creates an afterload mismatch state leading to LV remodeling.
- Angiotensin-converting enzyme inhibition effectively mitigates these adverse hemodynamic and cardiac effects.
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