title: Combined angiotensin II type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries.
abstract: We investigated the role of angiotensin II type 1 (AT1) and AT2 receptors, matrix metalloproteinases (MMPs), and extracellular matrix (ECM) components involved in vascular remodeling of resistance arteries induced by angiotensin II (Ang II). Sprague-Dawley rats received Ang II (120 ng/kg per minute SC) +/- the AT1 antagonist losartan (10 mg/kg per day PO), the AT1/AT2 antagonist Sar1-Ile8-Ang II (Sar-Ile; 10 microg/kg per minute SC), or hydralazine (25 mg/kg per day PO) for 7 days. Structure and mechanical properties of small mesenteric arteries were evaluated on a pressurized myograph. Ang II increased growth index (+21%), which was partially decreased by losartan (-11%) and abrogated by Sar-Ile. Hydralazine markedly increased growth index (+32%) despite systolic blood pressure (BP) lowering, suggesting a BP-independent effect of Ang II on vascular growth. Elastic modulus was increased by Sar-Ile compared with Ang II and control. Vascular type I collagen was reduced (P<0.05), whereas fibronectin increased significantly with Sar-Ile. Vascular tissue inhibitor of metalloproteinase-2 binding to MMP-2 was abrogated by Sar-Ile, but MMP-2 activity was significantly increased compared with losartan, Ang II, and controls. Thus, AT1 blockade exerted antigrowth effects and reduced stiffness of small resistance arteries by decreasing nonelastic fibrillar components (collagen and fibronectin). Concomitant AT1/AT2 blockade prevented growth, reduced collagen type I and elastin deposition but increased vascular stiffness, fibronectin, and MMP-2 activity. These results demonstrate opposing roles of AT1 receptors that increase fibronectin and vascular stiffness and AT2 receptors that decrease MMP-2 and increase elastin. Changes in vascular wall mechanics, ECM deposition, and MMP activity are thus modulated differentially by Ang II receptors.
authors.affiliation: Canadian Institutes of Health Research, Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Quebec, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: Brassard
authors.forename: Farhad
authors.initials: F
authors.lastname: Amiri
authors.forename: Ernesto L
authors.initials: EL
authors.lastname: Schiffrin
mesh_terms: D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D015153:Blotting, Western; D024042:Collagen Type I / Q000378:metabolism; D004548:Elasticity; D004549:Elastin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism / Q000502:physiology*; D014655:Vascular Resistance
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D024042:Collagen Type I; D005353:Fibronectins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D006830:Hydralazine; D004549:Elastin; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D020778:Matrix Metalloproteinase 2; D019808:Losartan