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. 2018 Feb;182:152-160.
doi: 10.1016/j.pharmthera.2017.08.012. Epub 2017 Sep 4.

Bevacizumab-induced Hypertension: Clinical Presentation and Molecular Understanding

Free PMC article

Bevacizumab-induced Hypertension: Clinical Presentation and Molecular Understanding

Megan Li et al. Pharmacol Ther. .
Free PMC article


Bevacizumab is a vascular endothelial growth factor-A-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of several types of cancer. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy and lead to other cardiovascular complications. The factors that contribute to interindividual variability in blood pressure response to bevacizumab treatment are not well understood. In this review, we outline research efforts to understand the mechanisms and pathophysiology of hypertension resulting from bevacizumab treatment. Moreover, we highlight current knowledge of the pharmacogenetics of bevacizumab-induced hypertension, which may be used to develop strategies to prevent or minimize this toxicity.

Keywords: Bevacizumab; Hypertension; Pharmacogenetics; VEGF.

Conflict of interest statement

Conflict of Interest statement

The authors declare that there are no conflicts of interest.


Figure 1
Figure 1. VEGF signaling and inhibition by bevacizumab
Vascular endothelial growth factor (VEGF) receptors are primarily expressed by endothelial cells. VEGFA binds both VEGFR1 and VEGFR2, although VEGFA-mediated angiogenesis is primarily through VEGFR2, while VEGFR1 functions primarily as a decoy receptor for VEGFA. Placental growth factor (PlGF) and VEGFB bind selectively to VEGFR1, and VEGFC and VEGFD bind to VEGFR3, a key regulator of lymphangiogenesis. Neuropilin co-receptors NRP1 and NRP2 also regulate VEGFR signaling. Binding of VEGF by bevacizumab prevents VEGFA-activated receptor signaling.
Figure 2
Figure 2. Mechanism of VEGF-mediated vasodilation
Activation of VEGF receptor 2 (VEGFR2) induces cell proliferation, migration and survival, and vascular permeability, leading to angiogenesis. Signaling through phospholipase C (PLC)-γ activates protein kinase C (PKC) by the generation of diacylglycerol (DAG) and increases the concentration of intracellular calcium (Ca2+) via inositol 1,4,5-triphosphate (IP3). PKC activation, increased Ca2+, and activation of the PI3K-Akt pathway lead to phosphorylation and activation of endothelial nitric oxide synthase (eNOS) and generation of nitric oxide (NO). PKC also activates the Ras/MEK/ERK pathway, which in turn upregulates cytosolic phospholipase A2 (cPLA2). cPLA2 releases arachidonic acid (AA) from phospholipids, which is acted on by cyclooxygenases (COX-1/COX-2) to generate prostaglandin H2 (PGH2), which is then converted to prostacyclin (PGI2) by prostacyclin synthase (PGIS). NO and PGI2 diffuse to adjacent smooth muscle cells, where NO activates soluble guanylate cyclase (sGC), leading to cGMP synthesis. PGI2 binds to prostacyclin receptors (IP), which activate adenylyl cyclase (AC) and increase cAMP synthesis. cGMP and cAMP lead to decreased intracellular Ca2+ concentrations, which induce vasorelaxation.
Figure 3
Figure 3. Possible pathophysiological mechanisms of bevacizumab-induced hypertension
Vascular endothelial growth factor (VEGF) blockade by bevacizumab and decreased VEGFR2 signaling contributes to systemic vasoconstriction and increased peripheral resistance as a result of endothelial dysfunction and possibly other vascular abnormalities. Inhibition of VEGF signaling may also alter renal structure and function, leading to inadequate renal sodium excretion and volume overload. Not all listed mechanisms are supported by substantial evidence.

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