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Endostatin Lowers Blood Pressure Via Nitric Oxide and Prevents Hypertension Associated with VEGF Inhibition

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Endostatin Lowers Blood Pressure Via Nitric Oxide and Prevents Hypertension Associated with VEGF Inhibition Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition Sarah B. Sunshinea,1, Susan M. Dallabridaa, Ellen Duranda, Nesreen S. Ismaila, Lauren Bazineta, Amy E. Birsnera, Regina Sohnb, Sadakatsu Ikedac, William T. Puc, Matthew H. Kulked, Kashi Javaheriana, David Zurakowskie,f, Judah M. Folkmana,2, and Maria Rupnicka,b Divisions of aVascular Biology and cCardiology and Departments of eAnesthesia and fSurgery, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115; bDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and dDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215 Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved May 28, 2012 (received for review April 2, 2012) Antiangiogenesis therapy has become a vital part of the arma- control. VEGF stimulates endothelial NO synthase (eNOS), mentarium against cancer. Hypertension is a dose-limiting toxicity resulting in NO production and lower BP (21, 22). Inhibiting for VEGF inhibitors. Thus, there is a pressing need to address the VEGF in animal studies reduces eNOS expression, leading to associated adverse events so these agents can be better used. The vasoconstriction and hypertension (23). In patients, VEGF in- hypertension may be mediated by reduced NO bioavailability fusion causes rapid NO release and hypotension (24). resulting from VEGF inhibition. We proposed that the hyperten- Endostatin (ES), a fragment of collagen XVIII on chromosome sion may be prevented by coadministration with endostatin (ES), 21, is an endogenous angiogenesis inhibitor (25, 26). This 183- an endogenous angiogenesis inhibitor with antitumor effects amino acid fragment causes tumor regression in a number of shown to increase endothelial NO production in vitro. We de- animal models (27, 28). Although the molecular pathways are not termined that Fc-conjugated ES promoted NO production in fully defined, major effects of ES signaling include inhibition of endothelial and smooth muscle cells. ES also lowered blood endothelial cell migration and survival and angiogenesis. In ad- pressure in normotensive mice and prevented hypertension in- dition, ES induces NO release by cultured endothelial cells and duced by anti-VEGF antibodies. This effect was associated with relaxation of ex vivo vascular rings (29, 30). Down syndrome higher circulating nitrate levels and was absent in eNOS-knockout patients have an extra copy of chromosome 21 and a negligible mice, implicating a NO-mediated mechanism. Retrospective study incidence of solid tumors (31). Although several genes likely MEDICAL SCIENCES of patients treated with ES in a clinical trial revealed a small but contribute to this cancer protection (32), it is intriguing to note significant reduction in blood pressure, suggesting that the find- that these patients have ES levels 1.6 times higher than those of ings may translate to the clinic. Coadministration of ES with VEGF the general population (33). Further, their BP is lower than age- inhibitors may offer a unique strategy to prevent drug-related matched controls (34, 35). These data suggested to us that ES may hypertension and enhance antiangiogenic tumor suppression. enhance the antiangiogenic benefits and lessen the hypertensive effects of VEGF inhibition. Such a finding would offer an ap- nhibiting angiogenesis has proven to be effective in treating proach to improve tolerance to VEGF inhibitors, enabling long- Idiseases dependent on new blood vessel growth. In cancer term treatment with reduced risk of cardiovascular adverse events. patients, antiangiogenic agents prolong progression-free survival Here we show that murine Fc-conjugated ES lowers BP in and improve response rates when used in combination with cy- mice via an NO-mediated mechanism and blocks the hyperten- totoxic chemotherapy (1). In macular degeneration and diabetic sive response to anti-VEGF antibodies. Further, we found fi retinopathy these agents reduce vision loss (2, 3). Consequently, a small but signi cant reduction in BP in patients treated with ES fi angiogenesis inhibitors have been approved in 29 countries thus as part of a clinical trial, suggesting that the nding in mice may far (4), and new applications continue to be explored. be translatable. These results support further investigation into VEGF is a potent angiogenesis stimulator clinically estab- antitumor effects of combined therapy. fi fi lished as an ef cacious target for inhibition. The rst Food and Results Drug Administration-approved angiogenesis inhibitor was bev- acizumab (Avastin), a monoclonal anti-VEGF antibody now ES Lowers BP in C57BL/6 Mice. Normotensive C57BL/6 mice were used to treat several types of cancer (colon, lung, renal, breast) treated with ES at various doses and schedules, and BP and ocular neovascularization. Unfortunately, the enthusiasm for responses were compared with vehicle (saline)-treated controls. All mice were injected daily for 5 d with either ES or saline; bevacizumab and other such inhibitors is tempered by the after a 2-d intervening break, the cycle was repeated. A slight emergence of treatment-limiting adverse cardiovascular effects. reduction in BP at the onset of the study was noted in all the Hypertension is the most common dose-limiting toxicity of groups, likely resulting from further acclimation. Thereafter, BP VEGF inhibitors (5–9). Incidence ranges from 15% to 60%, in the control group remained unchanged, whereas BP of the depending on drug- and patient-related factors still being defined ES-treated groups decreased in relation to dose and schedule (10–14). Early and aggressive initiation of antihypertensive ther- (Fig. 1). Mice receiving ES (4 mg/kg) biweekly had the smallest apy can help maintain the treatment schedule (15) and reduce complications (16, 17). However, baseline blood pressures (BP) often are not reestablished (18). Further, it appears that nearly all Author contributions: S.B.S., S.M.D., J.M.F., and M.R. designed research; S.B.S., S.M.D., patients experience some increase in BP, even if not frank hy- E.D., N.S.I., L.B., A.E.B., R.S., S.I., W.T.P., M.H.K., K.J., J.M.F., and M.R. performed re- pertension (19). This finding is concerning, given that changes in search; S.B.S., S.M.D., N.S.I., M.H.K., D.Z., J.M.F., and M.R. analyzed data; and S.B.S. and BP of as little as 5 mm Hg can significantly impact mortality (20). M.R. wrote the paper. As life expectancy for patients maintained on these newer anti- The authors declare no conflict of interest. tumor agents continues to improve, complications from the ac- This article is a PNAS Direct Submission. companying chronic BP elevations will likely accumulate. 1To whom correspondence should be addressed. E-mail: [email protected]. One widely held explanation for angiogenesis inhibitor-asso- 2Deceased January 14, 2008. ciated hypertension is based on the role of VEGF in NO regu- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. lation. NO is a potent vasodilator that plays a critical role in BP 1073/pnas.1203275109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1203275109 PNAS Early Edition | 1of6 Downloaded by guest on September 24, 2021 Fig. 1. Murine Fc-ES resulted in a dose-dependent reduction in systolic BP in C57BL/6 mice. The low-dose group received 4 mg/kg, 2 d/wk (on days 0, 3, 7, 10, 14, and 17) and had the smallest decrease in BP. The high-dose group received 4 mg/kg, 5 d/wk (on days 0–4, 7–11, and 14–18) and had the most stable BP reduction. The concentrated-dose group received the cumulative high weekly dose of 20 mg/kg administered in a single concentrated bolus once a week (on days 0, 7, and 14) and had the greatest declines in BP on the days following treatment; BP levels recovered thereafter. *P < 0.05. BP reductions, with nadirs of ∼10 mm Hg below controls on the day following treatment (e.g., days 1 and 18). BP rebounded to about 5 mm Hg below controls between drug doses. Mice treated with ES (4 mg/kg) for 5 d consecutively exhibited the most stable reduction in BP, to an average of 10 mm Hg below controls, and did not rebound during the 2-d treatment breaks. The last group, which received a cumulative weekly dose of 20 mg/kg as a single, concentrated bolus and had the most sig- nificant decline in BP, to nearly 20 mm Hg below control fol- lowing drug injections. The BP then recovered to baseline before the next dose. Endogenous and Exogenous ES Increases NO. Physiologic concen- trations of ES have been shown to increase NO production in endothelial cells and to decrease vascular tone in ex vivo studies Fig. 2. Murine Fc-ES administration (4 mg/kg, 5 d/wk) is associated with (A) (29). We found that murine Fc-ES significantly increased nitrite higher circulating nitrate levels (a measure of NO) and (B) lower systolic BP in production in microvascular (MS1) endothelial cells (P = 0.005) C57BL/6 mice as compared with saline-treated controls. (C) Circulating NO (Fig. S1A) and smooth muscle cells (P = 0.0004) (Fig. S1B) levels were higher in ES-overexpressing mice and were lower in collagen compared with the matched vehicle (saline) controls. Elevated XVIII/ES-knockout mice than in wild-type control mice. These findings cor- NO production by these vascular cells in response to ES in vivo related NO levels with endogenous and exogenous ES levels. would lead to lower BP. fi Serum nitrate levels were signi cantly higher in mice treated nearly 130 mm Hg compared with 105 mm Hg typically seen in P A with ES ( = 0.0003) (Fig.
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