Identifying mitigating strategies for endothelial cell dysfunction and hypertension in response to VEGF receptor inhibitors.

Autor:	Camarda ND; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, U.S.A.; Genetics, Molecular, and Cellular Biology Program, Tufts Graduate School of Biomedical Sciences, Boston, MA, U.S.A., Lu Q; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, U.S.A., Meola DM; Tufts Cummings School of Veterinary Medicine, North Grafton, MA, U.S.A., Man JJ; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, U.S.A.; Genetics, Molecular, and Cellular Biology Program, Tufts Graduate School of Biomedical Sciences, Boston, MA, U.S.A., Song Z; Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, MA, U.S.A., Travers RJ; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, U.S.A.; Division of Hematology Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, U.S.A., Lopez KE; Tufts Cummings School of Veterinary Medicine, North Grafton, MA, U.S.A., Powers SN; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, U.S.A., Papanastasiou M; Broad Institute, Boston, MA, U.S.A., DeRuff KC; Broad Institute, Boston, MA, U.S.A., Mullahoo J; Broad Institute, Boston, MA, U.S.A., Egri SB; Broad Institute, Boston, MA, U.S.A., Davison D; Broad Institute, Boston, MA, U.S.A., Sebastiani P; Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, MA, U.S.A., Eblen ST; Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, U.S.A., Buchsbaum R; Division of Hematology Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, U.S.A., Huggins GS; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, U.S.A.; Division of Cardiology, Tufts Medical Center, Boston, MA, U.S.A., London CA; Tufts Cummings School of Veterinary Medicine, North Grafton, MA, U.S.A., Jaffe JD; Broad Institute, Boston, MA, U.S.A., Upshaw JN; Division of Cardiology, Tufts Medical Center, Boston, MA, U.S.A., Yang VK; Tufts Cummings School of Veterinary Medicine, North Grafton, MA, U.S.A., Jaffe IZ; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, U.S.A.; Genetics, Molecular, and Cellular Biology Program, Tufts Graduate School of Biomedical Sciences, Boston, MA, U.S.A.
Jazyk:	angličtina
Zdroj:	Clinical science (London, England : 1979) [Clin Sci (Lond)] 2024 Sep 18; Vol. 138 (18), pp. 1131-1150.
DOI:	10.1042/CS20240537
Abstrakt:	Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. α-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such α-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects. (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze:	MEDLINE
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