title: Hemodynamic, vascular, and reproductive impact of FMS-like tyrosine kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse pregnancy.
abstract: To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling during pregnancy, mice were injected with anti-FLT1 neutralizing antibody (Ab) beginning on Gestational Day 8 or 12 and every other day thereafter until Day 18; vehicle-only injected mice served as controls. Uterine artery blood flow was measured with ultrasound on Days 13 and 18, and morphometric measurements of the uterine arcade were carried out on Day 19 to provide a measure of gestational vascular remodeling; reproductive performance was evaluated by determining litter size, resorption rates, and pup and placental weights. Ab injections beginning on Day 8 or Day 12 resulted in significant reductions of uterine artery peak systolic and diastolic flows at Days 13 and 18. In addition, normal reproductive function was compromised, as evidenced by a significant reduction in average number of viable pups along with enhanced resorption rates. Reproductive performance was also significantly compromised in this group, although less severely. There was no evidence of a reduction in main uterine artery diameters, though arterial distensibility was reduced, and the diameter of the main uterine vein was significantly smaller in the Ab-injected mice. Significant reductions in main uterine artery and segmental artery length were also noted. Placental and pup weights were similar in all the groups. FLT1 inhibition during murine pregnancy impaired blood flow to the fetal-placental unit, compromised several indices of vascular remodeling, reduced fecundity, and increased fetal reabsorptions. The effects of FLT1 inhibition are most pronounced when targeted during early pregnancy.
authors.affiliation: Center for Vascular Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eliyahu V
authors.initials: EV
authors.lastname: Khankin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mandala
authors.forename: Ilsley
authors.initials: I
authors.lastname: Colton
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: George
authors.initials: G
authors.lastname: Osol
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000502:physiology; D005260:Female; D005327:Fetal Resorption / Q000503:physiopathology; D005333:Fetus / Q000098:blood supply; D006439:Hemodynamics / Q000502:physiology*; D008098:Litter Size; D051379:Mice; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010920:Placenta / Q000098:blood supply; D021041:Placental Circulation / Q000502:physiology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D012098:Reproduction / Q000502:physiology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000187:drug effects
chemical_list: D000888:Antibodies, Anti-Idiotypic; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
references.citation: Nat Med. 2002 Aug;8(8):831-40
references.pmid: 12091877
references.citation: N Engl J Med. 2004 Feb 12;350(7):672-83
references.pmid: 14764923
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9349-54
references.pmid: 9689083
references.citation: Am J Obstet Gynecol. 1981 Dec 15;141(8):873-84
references.pmid: 6274196
references.citation: Reprod Sci. 2009 May;16(5):489-500
references.pmid: 19164479
references.citation: Am J Physiol. 1997 Feb;272(2 Pt 2):H851-8
references.pmid: 9124448
references.citation: Reprod Sci. 2009 Jun;16(6):596-604
references.pmid: 19318688
references.citation: Am J Physiol. 1985 May;248(5 Pt 2):H658-65
references.pmid: 2581458
references.citation: Am J Physiol. 1993 Jan;264(1 Pt 2):H78-85
references.pmid: 8430865
references.citation: Am J Obstet Gynecol. 1993 Jan;168(1 Pt 1):268-74
references.pmid: 8420338
references.citation: Arthritis Rheum. 2009 Feb;60(2):345-54
references.pmid: 19180491
references.citation: Anat Rec. 1975 May;182(1):61-5
references.pmid: 1155791
references.citation: Science. 1986 Jan 24;231(4736):405-7
references.pmid: 3941904
references.citation: J Clin Invest. 2003 Mar;111(5):649-58
references.pmid: 12618519
references.citation: J Biol Chem. 1994 Oct 28;269(43):26988-95
references.pmid: 7929439
references.citation: Am J Obstet Gynecol. 1993 Feb;168(2):697-705
references.pmid: 8438952
references.citation: Am J Obstet Gynecol. 1985 Mar 1;151(5):682-6
references.pmid: 3976768
references.citation: Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1381-7
references.pmid: 18192215
references.citation: J Vasc Res. 2012;49(1):43-9
references.pmid: 21985802
references.citation: Am J Obstet Gynecol. 1993 Dec;169(6):1507-9
references.pmid: 8267054
references.citation: Am J Physiol. 1997 Aug;273(2 Pt 2):H938-44
references.pmid: 9277513
references.citation: EMBO J. 2000 Aug 1;19(15):4064-73
references.pmid: 10921887
references.citation: J Dev Physiol. 1989 Aug;12(2):101-8
references.pmid: 2621336
references.citation: Circulation. 2011 Jun 21;123(24):2856-69
references.pmid: 21690502
references.citation: Am J Physiol. 1997 Sep;273(3 Pt 2):H1148-53
references.pmid: 9321801
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15637-42
references.pmid: 14668430
references.citation: Physiology (Bethesda). 2009 Feb;24:58-71
references.pmid: 19196652