Stretch induces mitogen-activated protein kinase activation and myogenic tone through 2 distinct pathways.
The aim of this study was to evaluate the involvement of the mitogen-activated protein kinase (ERK1/2) pathway in response to stretch in a blood vessel developing myogenic tone on stretch. Indeed, in resistance arteries and veins, the main effect of pressure is to induce a maintained vasoconstrictor (myogenic) tone. Isolated segments of rabbit facial vein were mounted in organ baths and submitted to isometric stretch. In this experimental model, myogenic tone was absent when the bath temperature was 33 degrees C. ERK1/2 activity was determined in each isolated segment by an in-gel kinase assay. Wall tension and ERK1/2 activity were measured in the same samples in the presence (39 degrees C) or in the absence of myogenic tone (33 degrees C). At 39 degrees C, a 5-mN wall tension induced myogenic tone (5.7+/-1.8 mN) and an increase in ERK1/2 activity (282+/-52% versus unstretched vessels, P<0.05). At 33 degrees C, in the absence of myogenic tone, ERK1/2 activity was similarly increased by stretch (254+/-35% versus unstretched vessels). The calcium-dependent and -independent protein kinase C (PKC) blocker Ro-31-8220 (5 x 10(-7) mol/L), but not the calcium-dependent PKC blocker Go-6976 (10(-6) mol/L), inhibited myogenic tone. However, ERK1/2 activity was not affected by either PKC blocker. Genistein (10(-7) mol/L), a general tyrosine kinase inhibitor, but not herbimycin A (5 x 10(-7) mol/L), a cSrc-family tyrosine kinase inhibitor, suppressed stretch-induced ERK1/2 activation (P<0.05) without affecting myogenic tone. Nifedipine (10(-6) mol/L), a voltage-dependent calcium entry inhibitor, and ryanodine (10(-6) mol/L), which depletes calcium stores, both inhibited ERK1/2 activity (113+/-12% and 121+/-7%, respectively; P<0. 05) without affecting myogenic tone. The mitogen-activated protein kinase kinase inhibitor PD 98059 (5 x 10(-6) mol/L) also inhibited ERK1/2 activation without affecting myogenic tone. The present results suggest that stretching the rabbit facial vein induced 2 distinct pathways, one leading to myogenic tone (via a non-calcium-dependent PKC activation) and one leading to ERK1/2 activation through a calcium-dependent pathway involving tyrosine kinase.
Loufrani
L
L
Institut National de la Santé et de la Recherche Médicale (INSERM) U 141, IFR6 Circulation Lariboisière, Université Paris VII, Paris, France.
Lehoux
S
S
Tedgui
A
A
Lévy
B I
BI
Henrion
D
D
D000818:Animals; D016227:Benzoquinones; D002227:Carbazoles / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009129:Muscle Tonus / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D011817:Rabbits; D017828:Rifabutin / Q000031:analogs & derivatives; D013696:Temperature; D014661:Vasoconstriction / Q000502:physiology*; D014680:Veins / Q000201:enzymology*
D016227:Benzoquinones; D002227:Carbazoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D047029:Lactams, Macrocyclic; D011809:Quinones; C081021:Go 6976; D017828:Rifabutin; C020754:herbimycin; D019833:Genistein; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C064758:Ro 31-8220