Vascular smooth muscle proliferation: synergistic interaction between serotonin and low density lipoproteins.
OBJECTIVE
The purpose of this study was to examine whether low density lipoproteins (LDLs) or mildly oxidized LDL (mox-LDL) are mitogens for vascular smooth muscle cells (VSMCs) and whether they can act synergistically with serotonin (5HT), a known mitogen for VSMC, in potentiating the proliferative effect of 5HT on VSMC.


BACKGROUND
Whether LDL or mox-LDL has a mitogenic effect on VSMC has been controversial. It is possible that LDL may not be mitogenic to VSMC but modification of LDL may confer mitogenic properties on LDL. A known mitogen for VSMC is 5HT that is released by aggregating platelets at sites of atherosclerotic changes or endothelial dysfunction. It is possible that LDL may interact with 5HT to enhance VSMC proliferation induced by 5HT.


METHODS
Growth arrested primary VSMCs were incubated with different concentrations of LDL or mox-LDL for 24 h followed by incubation with 5HT for another 24 h (mild oxidation of LDL was achieved by incubating LDL with Cu++ which increased the thiobarbituric acid product formation without a change in electrophoretic mobility). The increase in cell number or the amount of 3H-thymidine incorporated into the DNA was then measured.


RESULTS
Low density lipoprotein and mox-LDL induced significant VSMC proliferation by themselves and this effect was potentiated by 5HT. The 5HT2 receptor antagonist (LY281067) and pertussis toxin reversed only the proliferative effect of 5HT. Polyinosinic acid (poly-I), an inhibitor of scavenger receptors, did not inhibit the proliferative effect of LDL or mox-LDL or their synergistic interaction with 5HT.


CONCLUSIONS
These results suggest that LDL and mox-LDL act synergistically with 5HT in inducing VSMC proliferation. The synergistic interaction could be blocked by LY281067 and pertussis toxin but not by poly-I acid.
Koba
S
S
Showa University School of Medicine, Tokyo, Japan.
Pakala
R
R
Watanabe
T
T
Katagiri
T
T
Benedict
C R
CR
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000502:physiology*; D008237:Lysergic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008934:Mitogens; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects*; D037342:Pertussis Toxin; D011817:Rabbits; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D008077:Lipoproteins, LDL; D008934:Mitogens; D012702:Serotonin Antagonists; D010566:Virulence Factors, Bordetella; D012701:Serotonin; D037342:Pertussis Toxin; D008237:Lysergic Acid; C054583:sergolexole