title: TIMP3 is the primary TIMP to regulate agonist-induced vascular remodelling and hypertension.
abstract: OBJECTIVE
  Hypertension is accompanied by structural remodelling of vascular extracellular matrix (ECM). Tissue inhibitor of metalloproteinases (TIMPs) inhibits matrix metalloproteinases (MMPs) that degrade the matrix structural proteins. In response to a hypertensive stimulus, the balance between MMPs and TIMPs is altered. We examined the role of TIMPs in agonist-induced hypertension.
  
  
  RESULTS
  We subjected TIMP-knockout mice to angiotensin II (Ang II) infusion, and found that Ang-II-induced hypertension in TIMP1(-/-), TIMP2(-/-), and TIMP4(-/-) mice was comparable to wild-type (WT) mice, but significantly suppressed in TIMP3(-/-) mice. Ex vivo pressure myography analyses on carotid and mesenteric arteries revealed that Ang-II-infused TIMP3(-/-) arteries were more distensible with impaired elastic recoil compared with the WT group. The acute response to vasoconstriction and vasodilation was intact in TIMP3(-/-) mesenteric and carotid arteries. Mesenteric arteries from TIMP3(-/-)-Ang II mice exhibited a reduced media-to-lumen ratio, suppressed collagen and elastin levels, elevated elastase and gelatinase proteolytic activities compared with WT-Ang II. TIMP3(-/-)-Ang II carotid arteries also showed adverse structural remodelling. Treatment of mice with doxycycline, a matrix metalloproteinase inhibitor, improved matrix integrity in mesenteric and carotid arteries in TIMP3(-/-)-Ang II and differentially regulated elastin and collagen levels in WT-Ang II vs. TIMP3(-/-)-Ang II.
  
  
  CONCLUSIONS
  Our study demonstrates a critical role for TIMP3, among all TIMPs, is preserving arterial ECM in response to Ang II. It is critical to acknowledge that the suppressed Ang-II-induced hypertension in TIMP3(-/-) mice is not a protective mechanism but owing to adverse remodelling in arterial matrix.
authors.affiliation: Department of Physiology, University of Alberta, 474 HMRC, Edmonton, Alberta, Canada T6G 2S2.
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.forename: Jiwon
authors.initials: J
authors.lastname: Lee
authors.forename: Jude S
authors.initials: JS
authors.lastname: Morton
authors.forename: Abhijit
authors.initials: A
authors.lastname: Takawale
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.forename: Vijay
authors.initials: V
authors.lastname: Kandalam
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Wang
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
mesh_terms: D000804:Angiotensin II; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D014661:Vasoconstriction; D014664:Vasodilation; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D018093:Gelatinases; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C560825:Timp1 protein, mouse
keywords: Extracellular matrix; Hypertension; Tissue inhibitor of metalloproteinase; Vascular remodelling