Role of the Rhoa/Rho kinase system in flow-related remodeling of rat mesenteric small arteries in vivo.
In small arteries, a chronic blood flow reduction leads to inward hypotrophic remodeling, while a chronic blood flow elevation induces outward hypertrophic remodeling. The RhoA/Rho kinase system was shown to be modulated by shear stress, and to be involved in other kinds of vascular remodeling. The aim of this study was to investigate the role of RhoA/Rho kinase in flow-related small artery remodeling. Rat mesenteric small arteries were subjected to flow-modifying surgery. After 1, 2, 4, 16, and 32 days, the animals were sacrificed and small arteries were harvested. Messenger RNA was isolated and amplified. Using cDNA microarray analysis, the differential expression of >14,000 genes was analyzed, part of which was confirmed by RT-PCR. In vivo treatment with fasudil (3 mg/kg/day s.c.) was used to test the effect of Rho kinase inhibition. The main findings are that: (1) blood flow alteration modified the expression of approximately 5% of the genes by >2-fold, (2) flow reduction downregulated many RhoA-related cytoskeletal markers of smooth muscle cell phenotype, (3) many RhoA-related genes were rapidly (<1 day) regulated and (4) fasudil treatment potentiated the inward hypotrophic remodeling in response to chronically reduced flow. These results indicate the importance of the RhoA/Rho kinase system in flow-related small artery remodeling.
Wesselman
Jos P M
JP
Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
Kuijs
Robin
R
Hermans
J J Rob
JJ
Janssen
Ger M J
GM
Fazzi
Gregorio E
GE
van Essen
Helma
H
Evelo
Chris T A
CT
Struijker-Boudier
Harry A J
HA
De Mey
Jo G R
JG
D000818:Animals; D003285:Contractile Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D003285:Contractile Proteins; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein