title: SFlt-1 elevates blood pressure by augmenting endothelin-1-mediated vasoconstriction in mice.
abstract: OBJECTIVE
  Scavenging of vascular endothelial growth factor (VEGF) elevates blood pressure (BP) in patients receiving anti-angiogenic therapy. Similarly, inhibition of circulation VEGF by its soluble receptor fms-like tyrosine kinase-1 (sFlt-1) underlies BP elevation in pre-eclampsia. Both phenotypes are characterized by augmented production of endothelin-1 (ET-1), suggesting a role for ET-1 in anti-angiogenic hypertension. We aimed to assess the effect of VEGF inhibition on ET-1-induced contractility and downstream ET-1 signaling.
  
  
  RESULTS
  Male C57BL/6N mice were treated with either sFlt-1 or vehicle and BP was assessed via tail-cuff. Mean arterial pressure of sFlt-1-treated mice markedly increased compared to vehicle-treated controls (N = 11-12, p<0.05). After sacrifice, carotid and mesenteric arteries were isolated for isometric tension measurements. ET-1-induced contractions were similar in mesenteric arteries of vehicle and sFlt-1-treated mice, but augmented in carotid segments of sFlt-1-treated mice compared to controls (N = 9-10, p<0.05). The increased contraction in carotid segments could be completely abrogated by the cyclooxygenase (COX) inhibitor indomethacin (N = 9-10, p<0.05), indicating heightened prostaglandin-mediated vasoconstriction. This was associated with a shift towards procontractile ETB signaling in sFlt-1-treated mice, possibly explaining the increased ET-1-induced prostaglandin-mediated vasoconstriction. In line with the ex vivo findings, sFlt-1-induced BP elevation could be prevented in vivo by oral treatment with either a high-dose of the COX inhibitor aspirin (N = 7) or with picotamide (N = 9), a dual thromboxane A2 synthase inhibitor and receptor antagonist.
  
  
  CONCLUSIONS
  VEGF inhibition augments the pressor response to ET-1. The cyclooxygenase-thromboxane signaling route downstream of ET-1 might be a possible target to prevent BP elevation during VEGF inhibition.
authors.affiliation: Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Fouad
authors.initials: F
authors.lastname: Amraoui
authors.affiliation: Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Léon
authors.initials: L
authors.lastname: Spijkers
authors.affiliation: Women's and Children's Clinic, Academic Medical Center, Amsterdam, The Netherlands; Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Hajar
authors.initials: H
authors.lastname: Hassani Lahsinoui
authors.affiliation: Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Liffert
authors.initials: L
authors.lastname: Vogt
authors.affiliation: Women's and Children's Clinic, Academic Medical Center, Amsterdam, The Netherlands; Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: van der Post
authors.affiliation: Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Stephan
authors.initials: S
authors.lastname: Peters
authors.affiliation: Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: Afink
authors.affiliation: Women's and Children's Clinic, Academic Medical Center, Amsterdam, The Netherlands; Reproductive Biology Laboratory, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Carrie
authors.initials: C
authors.lastname: Ris-Stalpers
authors.affiliation: Department of Internal and Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Bert-Jan
authors.initials: BJ
authors.lastname: van den Born
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D042461:Vascular Endothelial Growth Factor A; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1