title: Tissue Inhibitor of Metalloproteinase 1 Influences Vascular Adaptations to Chronic Alterations in Blood Flow.
abstract: Remodeling of the skeletal muscle microvasculature involves the coordinated actions of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitor of metalloproteinases (TIMPs). We hypothesized that the loss of TIMP1 would enhance both ischemia and flow-induced vascular remodeling by increasing MMP activity. TIMP1 deficient (Timp1-/-) and wild-type (WT) C57BL/6 mice underwent unilateral femoral artery (FA) ligation or were treated with prazosin, an alpha-1 adrenergic receptor antagonist, in order to investigate vascular remodeling to altered flow. Under basal conditions, Timp1-/-mice had reduced microvascular content as compared to WT mice. Furthermore, vascular remodeling was impaired in Timp1-/-mice. Timp1-/-mice displayed reduced blood flow recovery in response to FA ligation and no arteriogenic response to prazosin treatment. Timp1-/-mice failed to undergo angiogenesis in response to ischemia or prazosin, despite maintaining the capacity to increase VEGF-A and eNOS mRNA. Vascular permeability was increased in muscles of Timp1-/-mice in response to both prazosin treatment and FA ligation, but this was not accompanied by greater MMP activity. This study highlights a previously undescribed integral role for TIMP1 in both vascular network maturation and adaptations to ischemia or alterations in flow. J. Cell. Physiol. 232: 831-841, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Mandel
authors.affiliation: School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Uchida
authors.affiliation: School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nwadozi
authors.affiliation: School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Armin
authors.initials: A
authors.lastname: Makki
authors.affiliation: School of Kinesiology and Health Science and the Muscle Health Research Centre, York University, Toronto, Ontario, Canada.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Haas
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001775:Blood Circulation / Q000187:drug effects / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects; D005121:Extremities / Q000098:blood supply / Q000473:pathology; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D007511:Ischemia / Q000473:pathology; D008026:Ligation; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases; D011224:Prazosin