title: Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase.
abstract: BACKGROUND
  Aortic stiffening commonly occurs in hypertension and further elevates systolic pressure. Hypertension is also associated with vascular inflammation and increased mechanical stretch. The interplay between inflammation, mechanical stretch, and aortic stiffening in hypertension remains undefined.
  
  
  OBJECTIVE
  Our aim was to determine the role of inflammation and mechanical stretch in aortic stiffening.
  
  
  RESULTS
  Chronic angiotensin II infusion caused marked aortic adventitial collagen deposition, as quantified by Masson trichrome blue staining and biochemically by hydroxyproline content, in wild-type but not in recombination activating gene-1-deficient mice. Aortic compliance, defined by ex vivo measurements of stress-strain curves, was reduced by chronic angiotensin II infusion in wild-type mice (P<0.01) but not in recombination activating gene-1-deficient mice (P<0.05). Adoptive transfer of T-cells to recombination activating gene-1-deficient mice restored aortic collagen deposition and stiffness to values observed in wild-type mice. Mice lacking the T-cell-derived cytokine interleukin 17a were also protected against aortic stiffening. In additional studies, we found that blood pressure normalization by treatment with hydralazine and hydrochlorothiazide prevented angiotensin II-induced vascular T-cell infiltration, aortic stiffening, and collagen deposition. Finally, we found that mechanical stretch induces the expression of collagen 1α1, 3α1, and 5a1 in cultured aortic fibroblasts in a p38 mitogen-activated protein kinase-dependent fashion, and that inhibition of p38 prevented angiotensin II-induced aortic stiffening in vivo. Interleukin 17a also induced collagen 3a1 expression via the activation of p38 mitogen-activated protein kinase.
  
  
  CONCLUSIONS
  Our data define a pathway in which inflammation and mechanical stretch lead to vascular inflammation that promotes collagen deposition. The resultant increase in aortic stiffness likely further worsens systolic hypertension and its attendant end-organ damage.
authors.affiliation: From the Division of Clinical Pharmacology (J.W., S.R.T., A.K., D.W.T., M.A.S., L.X., M.S.M., W.C., D.G.H), and Departments of Medicine and Pharmacology (J.W., D.G.H.), Vanderbilt University, Nashville, TN; and Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt (M.A.S.).
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Salim R
authors.initials: SR
authors.lastname: Thabet
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Trott
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Saleh
authors.forename: Liang
authors.initials: L
authors.lastname: Xiao
authors.forename: Meena S
authors.initials: MS
authors.lastname: Madhur
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D019264:Adoptive Transfer; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001018:Aortic Diseases / Q000378:metabolism* / Q000503:physiopathology; D015704:CD4 Antigens / Q000235:genetics; D016827:CD8 Antigens / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007249:Inflammation / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013314:Stress, Mechanical; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D059289:Vascular Stiffness / Q000502:physiology*; D014657:Vasculitis / Q000378:metabolism* / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D018398:Homeodomain Proteins; D020381:Interleukin-17; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C064658:RAG-1 protein; D003094:Collagen; D004549:Elastin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: inflammation