Genetic interference with peroxisome proliferator-activated receptor γ in smooth muscle enhances myogenic tone in the cerebrovasculature via A Rho kinase-dependent mechanism.
Myogenic responses by resistance vessels are a key component of autoregulation in brain, thus playing a crucial role in regulating cerebral blood flow and protecting the blood-brain barrier against potentially detrimental elevations in blood pressure. Although cerebrovascular disease is often accompanied by alterations in myogenic responses, mechanisms that control these changes are poorly understood. Peroxisome proliferator-activated receptor γ has emerged as a regulator of vascular tone. We hypothesized that interference with peroxisome proliferator-activated receptor γ in smooth muscle would augment myogenic responses in cerebral arteries. We studied transgenic mice expressing a dominant-negative mutation in peroxisome proliferator-activated receptor γ selectively in smooth muscle (S-P467L) and nontransgenic littermates. Myogenic tone in middle cerebral arteries from S-P467L was elevated 3-fold when compared with nontransgenic littermates. Rho kinase is thought to play a major role in cerebrovascular disease. The Rho kinase inhibitor, Y-27632, abolished augmented myogenic tone in middle cerebral arteries from S-P467L mice. CN-03, which modifies RhoA making it constitutively active, elevated myogenic tone to ≈60% in both strains, via a Y-27632-dependent mechanism. Large conductance Ca(2+)-activated K(+) channels (BKCa) modulate myogenic tone. Inhibitors of BKCa caused greater constriction in middle cerebral arteries from nontransgenic littermates when compared with S-P467L. Expression of RhoA or Rho kinase-I/II protein was similar in cerebral arteries from S-P467L mice. Overall, the data suggest that peroxisome proliferator-activated receptor γ in smooth muscle normally inhibits Rho kinase and promotes BKCa function, thus influencing myogenic tone in resistance arteries in brain. These findings have implications for mechanisms that underlie large- and small-vessel disease in brain, as well as regulation of cerebral blood flow.
From the Departments of Internal Medicine (T.M.D.S., C.D.S, F.M.F.) and Pharmacology (P.K., C.P., C.D.S., F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; and Veterans Affairs Healthcare System, Iowa City, IA (F.M.F.).
T Michael
TM
De Silva
From the Departments of Internal Medicine (T.M.D.S., C.D.S, F.M.F.) and Pharmacology (P.K., C.P., C.D.S., F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; and Veterans Affairs Healthcare System, Iowa City, IA (F.M.F.).
Pimonrat
P
Ketsawatsomkron
From the Departments of Internal Medicine (T.M.D.S., C.D.S, F.M.F.) and Pharmacology (P.K., C.P., C.D.S., F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; and Veterans Affairs Healthcare System, Iowa City, IA (F.M.F.).
Christopher
C
Pelham
From the Departments of Internal Medicine (T.M.D.S., C.D.S, F.M.F.) and Pharmacology (P.K., C.P., C.D.S., F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; and Veterans Affairs Healthcare System, Iowa City, IA (F.M.F.).
Curt D
CD
Sigmund
From the Departments of Internal Medicine (T.M.D.S., C.D.S, F.M.F.) and Pharmacology (P.K., C.P., C.D.S., F.M.F.), Francois M. Abboud Cardiovascular Center, The University of Iowa Carver College of Medicine; and Veterans Affairs Healthcare System, Iowa City, IA (F.M.F.). frank-faraci@uiowa.edu.
Frank M
FM
Faraci
D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D064791:Desoxycorticosterone Acetate / Q000633:toxicity; D004790:Enzyme Induction; D020869:Gene Expression Profiling; D005799:Genes, Dominant; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D047495:PPAR gamma / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012965:Sodium Chloride / Q000633:toxicity; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D054460:rho-Associated Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020742:rhoA GTP-Binding Protein
C530995:BKCa protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D047495:PPAR gamma; D012965:Sodium Chloride; D019789:Tetraethylammonium; D064791:Desoxycorticosterone Acetate; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
cerebral arteries; cerebrovascular circulation; potassium channels; protein kinase C