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Growth factors downregulate vascular smooth muscle thromboxane receptors independent of cell growth
1Department of Medicine/Cardiology, University of Cincinnati College of Medicine, Ohio 45267.
Abstract:
Growth factors, in addition to being mitogenic, may modulate vascular smooth muscle differentiation. We tested whether serum or defined growth factors could regulate thromboxane A2 (TxA2) receptors in cultured rabbit aorta smooth muscle cells. Fetal bovine serum (10%) stimulated cell proliferation and DNA synthesis in subconfluent cell cultures. Binding of the thromboxane A2 agonist [1S-(1 alpha 2 beta(5Z),3 alpha(1E,3S),4 alpha)]-7-[3-(3-hydroxy-4-p- iodophenoxy-1-butenyl)-7-oxabicyclo[2.2.1]heptan-2-yl]-5-hep tenoic acid showed a 41% decrease in TxA2 receptors in cells treated with 10% serum compared with serum-deprived (0.1%) controls. Receptor downregulation by serum was gradually reversible upon serum withdrawal. Compared with serum-deprived cells, those exposed to 10% serum also had diminished TxA2-stimulated phosphatidylinositol hydrolysis. Regulatory actions of serum on TxA2 receptors were distinguished from mitogenic effects with heparin, which prevented cell growth but did not inhibit serum-induced downregulation of TxA2 receptors. Furthermore, low concentrations of platelet-derived growth factor and basic fibroblast growth factor decreased TxA2 receptors without stimulating cell proliferation or DNA synthesis. These observations describe a previously unrecognized regulatory action of growth factors on a vascular smooth muscle vasoconstrictor receptor, an action which is independent of effects on cell proliferation or DNA synthesis.
Insights
Growth factors, including serum, downregulate thromboxane A2 (TxA2) receptors in vascular smooth muscle cells. This effect on TxA2 receptors is independent of cell proliferation or DNA synthesis.
Area of Science:
- Vascular Biology
- Cell Signaling
- Smooth Muscle Physiology
Background:
- Growth factors influence vascular smooth muscle cell (VSMC) differentiation and function.
- Thromboxane A2 (TxA2) is a potent vasoconstrictor that acts via specific receptors on VSMCs.
Purpose of the Study:
- To investigate the regulatory effects of serum and defined growth factors on TxA2 receptors in cultured rabbit aorta smooth muscle cells.
- To determine if growth factor-induced modulation of TxA2 receptors is linked to mitogenic activity.
Main Methods:
- Cultured rabbit aorta smooth muscle cells were treated with fetal bovine serum (FBS) or specific growth factors.
- Thromboxane A2 receptor density was measured using radioligand binding assays.
- TxA2-stimulated phosphatidylinositol hydrolysis was assessed.
- Cell proliferation and DNA synthesis were monitored.
Main Results:
- 10% FBS significantly decreased TxA2 receptor density (41%) and attenuated TxA2-stimulated phosphatidylinositol hydrolysis.
- FBS-induced downregulation of TxA2 receptors was reversible upon serum withdrawal.
- Heparin inhibited cell proliferation but not serum-induced receptor downregulation.
- Platelet-derived growth factor and basic fibroblast growth factor reduced TxA2 receptors without affecting cell proliferation or DNA synthesis.
Conclusions:
- Growth factors, independent of their mitogenic effects, can downregulate TxA2 receptors in vascular smooth muscle cells.
- This represents a novel regulatory mechanism for vasoconstrictor receptors in the vasculature.
- These findings have implications for understanding vascular tone regulation and disease pathogenesis.
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