Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation.
Arterial hypertension (HT) has been reported in all studies involving bevacizumab, an antiangiogenic agent designed to target vascular endothelial growth factor (VEGF). The mechanism underlying bevacizumab-related HT is not yet clearly understood. As far as endothelial dysfunction and microvascular rarefaction are hallmarks in all forms of HT, we tested the hypothesis that anti-VEGF therapy could alter the microcirculation in nontumor tissues and, thus, result in an increase in blood pressure (BP). We used intravital video microscopy to measure dermal capillary densities in the dorsum of the fingers. Microvascular endothelial function was assessed by laser Doppler flowmetry combined with iontophoresis of pilocarpine (acetylcholine analogue). All measurements were carried out in 18 patients before and after a 6-month treatment with bevacizumab (mean cumulative dose: 3.16 +/- 0.90 g). Mean BP was increased after 6 months of therapy compared with baseline, from 129 +/- 13/75 +/- 7 mmHg to 145 +/- 17/82 +/- 7 mmHg for systolic BP and diastolic BP, respectively (P < 0.0001). Compared with the baseline, mean dermal capillary density at 6 months was significantly lower (75 +/- 12 versus 83 +/- 13/mm(2); P < 0.0001), as well as pilocarpine-induced vasodilation (P < 0.05). Thus, bevacizumab treatment resulted in endothelial dysfunction and capillary rarefaction; both changes are closely associated and could be responsible for the rise in BP observed in most patients.
Mourad
J-J
JJ
Avicenne Hospital Assistance Publique-Hôpitaux de Paris, Paris XIII University (EA3412), Bobigny, France.
des Guetz
G
G
Debbabi
H
H
Levy
B I
BI
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D001794:Blood Pressure / Q000187:drug effects*; D002196:Capillaries / Q000187:drug effects; D018678:Cholinergic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D005385:Fingers / Q000098:blood supply; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006973:Hypertension / Q000139:chemically induced*; D007478:Iontophoresis; D017078:Laser-Doppler Flowmetry; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D018715:Microscopy, Video; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010862:Pilocarpine / Q000008:administration & dosage / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018678:Cholinergic Agents; D010862:Pilocarpine; D000068258:Bevacizumab