Mitogenic effects of ATP on vascular smooth muscle cells vs. other growth factors and sympathetic cotransmitters.
The sympathetic nervous system has been shown to exert a trophic influence on vascular smooth muscle cells (VSMC). Therefore, we studied the growth-regulating effects of the sympathetic cotransmitters ATP, neuropeptide Y (NPY), and norepinephrine (NE). ATP in concentrations of 1-100 microM greatly increased the incorporation of [3H]thymidine in VSMC from rat aorta and vena cava. ATP also increased cell number and total protein content. The maximal effect on [3H]thymidine incorporation was greater than for epidermal growth factor (20 ng/ml) or insulin (1 microgram/ml) and approximately one-half that of 10% fetal calf serum. The potency series of other nucleotides and analogues of ATP was ATP > beta, gamma-methyleneATP (AMP-PCP) > ADP > adenosine > alpha, beta- methyleneATP (AMP-CPP) > 2-methylthioATP, indicating involvement of a P2 receptor, however, it does not meet proposed pharmacological criteria of either the P2x or P2y subclass. Several proposed P2 receptor antagonists were without effect. The effect of ATP could be mediated by a "nucleotide receptor," since UTP also stimulated [3H]thymidine incorporation. In our model, there was a strong correlation between the mitogenic effects of ATP, AMP-CPP, AMP-PCP, and UTP and their ability to stimulate influx of extracellular Ca2+ (Ca2+o). Moreover, the mitogenic effect of ATP was increased by high concentrations of Ca2+o. Taken together with data showing the lack of involvement of several other second-messenger systems, this indicates a critical role for Ca2+o in mediating the mitogenic effects of ATP. Amiloride, known to inhibit the action of several growth factors, also inhibited ATP-induced mitogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Erlinge
D
D
Department of Internal Medicine, University of Lund, Sweden.
Yoo
H
H
Edvinsson
L
L
Reis
D J
DJ
Wahlestedt
C
C
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002414:Cations, Monovalent / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000037:antagonists & inhibitors; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D009478:Neuropeptide Y / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology*; D011687:Purines / Q000037:antagonists & inhibitors / Q000378:metabolism; D015290:Second Messenger Systems
D002414:Cations, Monovalent; D006133:Growth Substances; D007473:Ion Channels; D008934:Mitogens; D009478:Neuropeptide Y; D011687:Purines; D000255:Adenosine Triphosphate; D002118:Calcium; D009638:Norepinephrine