Dysfunction of endothelial and smooth muscle cells in small arteries of a mouse model of Marfan syndrome.
OBJECTIVE
Marfan syndrome, a connective tissue disorder caused by mutations in FBN1 encoding fibrillin-1, results in life-threatening complications in the aorta, but little is known about its effects in resistance vasculature.


METHODS
Second-order mesenteric arteries from mice at 3, 6 and 10 months of age (n= 30) heterozygous for the Fbn1 allele encoding a cysteine substitution (Fbn1(C1039G/+)) were compared with those from age-matched control littermates.


RESULTS
Stress-strain curves indicated that arterial stiffness was increased at 6 and 10 months of age in Marfan vessels. Isometric force measurement revealed that contraction in response to potassium (60 mM)-induced membrane depolarization was decreased by at least 28% in Marfan vessels at all ages, while phenylephrine (3 microM)-induced contraction was reduced by at least 40% from 6 months. Acetylcholine-induced relaxation in Marfan vessels was reduced to 70% and 45% of control values, respectively, at 6 and 10 months. Sensitivity to sodium nitroprusside was reduced at 6 months (pEC(50)= 5.64 +/- 0.11, control pEC(50)= 7.34 +/- 0.04) and 10 months (pEC(50)= 5.99 +/- 0.07, control pEC(50)= 6.99 +/- 0.14). Pretreatment with N(omega)-Nitro-L-arginine methyl ester (200 microM) had no effect on acetylcholine-induced relaxation in Marfan vessels, but reduced vasorelaxation in control vessels to 57% of control values. Addition of indomethacin (10 microM) and catalase (1000 U.mL(-1)) further inhibited vasorelaxation in Marfan vessels to a greater degree compared with control vessels.


CONCLUSIONS
Pathogenesis of Marfan syndrome in resistance-sized arteries increases stiffness and impairs vasomotor function.
Syyong
H T
HT
Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, Canada.
Chung
A W Y
AW
Yang
H H C
HH
van Breemen
C
C
D000109:Acetylcholine / Q000494:pharmacology; D000367:Age Factors; D000483:Alleles; D000818:Animals; D004195:Disease Models, Animal; D004548:Elasticity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D000071838:Fibrillin-1; D000071837:Fibrillins; D008382:Marfan Syndrome / Q000235:genetics / Q000503:physiopathology*; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology*; D009599:Nitroprusside / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D054392:Adipokines
D000109:Acetylcholine; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D009599:Nitroprusside; D010656:Phenylephrine; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C000605724:Fbn1 protein, mouse; D054392:Adipokines