Activation of resistance arteries with endothelin-1: from vasoconstriction to functional adaptation and remodeling.
Remodeling of resistance arteries is a key feature in hypertension. We studied the transition of vasoconstriction to remodeling in isolated rat skeletal muscle arterioles. Arterioles activated with 10 nM endothelin-1 showed functional adaptation when kept at low distension in a wire myograph setup, where contractile properties shifted towards a smaller lumen diameter after 1 day. Pressurized arteries kept in organoid culture showed physical inward remodeling after 3-day activation with 10 nM endothelin-1, characterized by a reduction in relaxed diameter without a change in the wall cross-sectional area (eutrophic remodeling). The relaxed lumen diameter (at 60 mm Hg) decreased from 169 +/- 5 (day 0) to 155 +/- 4 microm (day 3). An antibody directed to the beta(3)-integrin subunit (but not one directed to the beta(1)-integrin subunit) enhanced remodeling, from a reduction in relaxed diameter at 60 mm Hg of 15 +/- 2.4 to 22 +/- 1.8 microm (both on day 3). Collagen gel contraction experiments showed that the antibody directed to the beta(3)-integrin subunit enhanced the compaction of collagen by smooth muscle cells, from 83 +/- 1.5 to 68 +/- 1.5% of the initial gel diameter. In conclusion, these data show that inward eutrophic remodeling is a response to sustained contraction, which may involve collagen reorganization through beta(3)-integrins.
Bakker
Erik N T P
EN
Department of Pharmacology, University of Aarhus, Aarhus, Denmark. n.t.bakker@amc.uva.nl
Buus
Carsten L
CL
VanBavel
Ed
E
Mulvany
Michael J
MJ
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology*; D005109:Extracellular Matrix / Q000378:metabolism; D019012:Integrin beta1 / Q000276:immunology / Q000378:metabolism; D039661:Integrin beta3 / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
D000911:Antibodies, Monoclonal; D019332:Endothelin-1; D019012:Integrin beta1; D039661:Integrin beta3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases