Angiotensin II stimulates DNA and protein synthesis in vascular smooth muscle cells from human arteries: role of extracellular signal-regulated kinases
Rm. Touyz et al., Angiotensin II stimulates DNA and protein synthesis in vascular smooth muscle cells from human arteries: role of extracellular signal-regulated kinases, J HYPERTENS, 17(7), 1999, pp. 907-916
Citations number
52
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
Objective This study investigates the growth effects and associated signali
ng pathways of angiotensin II (Ang II) in human vascular smooth muscle cell
s.
Methods Cultured vascular smooth muscle cells derived from resistance arter
ies (< 300 mu m diameter) from subcutaneous gluteal biopsies of healthy sub
jects (n = 6) and human aortic vascular smooth muscle cells were used. Cell
s were studied between passages 3 and 6. Both H-3-thymidine and H-3-leucine
incorporation were measured as indices of vascular smooth muscle cell hype
rplasia (DNA synthesis) and cell hypertrophy (protein synthesis), respectiv
ely, Growth effects of Ang II (10(-12) - 10(-6) mol/l), in the absence and
presence of 10(-5) mol/l losartan (AT(1) antagonist) and PD123319 (AT(2) an
tagonist), were determined. Ang II-induced effects were compared to those o
f endothelin-1. To determine whether extracellular signal-regulated kinase
(ERK)-dependent pathways play a role in Ang II-mediated growth, cells were
pretreated with the selective ERK kinase (MEK) inhibitor, PD98059 (10-5 mol
/l), ERK activation was determined by Western blot in the absence and prese
nce of PD98059,
Results Ang II dose-dependently increased 3H-thymidine incorporation in cel
ls from aorta (E-max = 276 +/- 10.4% of control) and resistance arteries (E
-max = 284 +/- 5.1% of control). Ang II also stimulated 3H-leucine incorpor
ation in cells from aorta (E-max = 162 +/- 11.6 of control) and resistance
arteries (E-max 175 +/- 10% of control). Unlike Ang II, endothelin-1 failed
to significantly alter cellular growth, except at high concentrations (> 1
0(-7) mol/l), where it had a weak stimulatory effect. Losartan, but not PD1
23319, blocked Ang II-stimulated growth responses. Ang II significantly inc
reased phosphorylation of ERK-1 and ERK-2, with maximum responses obtained
at 5 min. PD98059 inhibited Ang II-stimulated ERK activity and abrogated ag
onist-induced DNA and protein synthesis. Losartan, but not PD123319 inhibit
ed Ang II-induced phosphorylation of ERK-1 and ERK-2,
Conclusions Ang II stimulates both hyperplasia and hypertrophy in vascular
smooth muscle cells from human arteries. These growth effects are mediated
via Ang II receptors of the AT(1) subtype that are linked to ERK-dependent
signaling pathways. I Hypertens 1999, 17:907-916 (C) Lippincott Williams &
Wilkins.