Smooth muscle dysfunction in resistance arteries of the staggerer mouse, a mutant of the nuclear receptor RORalpha.
Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily. The mouse mutant staggerer (sg/sg) carries a deletion within the RORalpha gene. RORalpha plays a major role in cellular differentiation during development and growth. In the present study, we found a lower mean arterial blood pressure in sg/sg than in +/+ mice (80.1+/-1.2 and 87.0+/-0.9 mm Hg, respectively; P<0.0002) and a smaller increase in blood pressure after in vivo injections of phenylephrine. To elucidate the mechanisms responsible for this phenotype, we investigated the vascular reactivity of large vessels (aorta and carotid arteries) and small resistance mesenteric arteries in response to mechanical forces or vasoactive agents. Arteries from sg/sg and +/+ mice were studied in vitro in arteriographs. Vascular responses of large vessels to all stimuli were similar in both groups. However, we found a markedly altered vascular function in mesenteric arteries from sg/sg mice. Flow-induced dilation, pressure-induced myogenic tone, responses to endothelium-dependent or -independent vasodilators, and responses to vasoconstrictors were significantly reduced in sg/sg compared with +/+ mice. We also determined by Western blot analysis the expression of smooth muscle (SM)-myosin, calponin, and heavy (h)-caldesmon, in large and small arteries of sg/sg and +/+ mice, and found a marked decrease in the expression of these contractile proteins in mesenteric arteries of sg/sg mice. Our findings provide the first evidence that functional RORalpha is required for normal contractile phenotype of smooth muscle cells (SMCs) in small resistance arteries and suggest that RORalpha might be involved in the differentiation of SMCs in mesenteric arteries.
Besnard
Sandrine
S
INSERM U541, IFR Circulation-Paris 7, Université Paris 7, Paris, France.
Bakouche
Joëlle
J
Lemaigre-Dubreuil
Yolande
Y
Mariani
Jean
J
Tedgui
Alain
A
Henrion
Daniel
D
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008840:Microfilament Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D024745:Smooth Muscle Myosins / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014654:Vascular Patency / Q000187:drug effects / Q000235:genetics; D014655:Vascular Resistance / Q000235:genetics*; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D000096985:Calponins
D002135:Calcium-Binding Proteins; D002148:Calmodulin-Binding Proteins; D008840:Microfilament Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D012701:Serotonin; D024745:Smooth Muscle Myosins; D015534:Trans-Activators; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000096985:Calponins