RhoA guanine exchange factor expression profile in arteries: evidence for a Rho kinase-dependent negative feedback in angiotensin II-dependent hypertension.
Sustained overactivation of RhoA is a common component for the pathogenesis of several cardiovascular disorders, including hypertension. Although activity of Rho proteins depends on Rho exchange factors (Rho-GEFs), the identity of Rho-GEFs expressed in vascular smooth muscle cells (VSMC) and participating in the control of Rho protein activity and Rho-dependent functions remains unknown. To address this question, we analyzed by quantitative RT-PCR the expression profile of 28 RhoA-GEFs in arteries of normotensive (saline-treated) and hypertensive (ANG II-treated) rats. Sixteen RhoA-GEFs were downregulated in mesenteric arteries of hypertensive rats, among which nine are also downregulated in cultured VSMC stimulated by ANG II (100 nM, 48 h), suggesting a direct effect of ANG II. Inhibition of type 1 ANG II receptors (losartan, 1 μM) or Rho kinase (fasudil, 10 μM) prevented ANG II-induced RhoA-GEF downregulation. Functionally, ANG II-induced downregulation of RhoA-GEFs is associated with decreased Rho kinase activation in response to endothelin-1, norepinephrine, and U-46619. This work thus identifies a group of RhoA-GEFs that controls RhoA and RhoA-dependent functions in VSMC, and a negative feedback of RhoA/Rho kinase activity on the expression of these RhoA-GEFs that may play an adaptative role to limit RhoA/Rho kinase activation.
Institut National de Santé et de Recherche Médicale, UMR S1087, Nantes, France.
Chrystelle
C
Cario-Toumaniantz
David
D
Ferland-McCollough
Gilliane
G
Chadeuf
Gilles
G
Toumaniantz
Marianne
M
Rodriguez
Jean-Pierre
JP
Galizzi
Brian
B
Lockhart
Antoine
A
Bril
Elizabeth
E
Scalbert
Gervaise
G
Loirand
Pierre
P
Pacaud
D000804:Angiotensin II / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001158:Arteries / Q000378:metabolism; D015153:Blotting, Western; D025461:Feedback, Physiological / Q000502:physiology*; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D034741:RNA, Small Interfering; D051381:Rats; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D054460:rho-Associated Kinases / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; D000804:Angiotensin II; D054460:rho-Associated Kinases