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Regulatory effects of platelet-derived growth factor-AA homodimer on migration of vascular smooth muscle cells
N Koyama1, N Morisaki, Y Saito
1Second Department of Internal Medicine, School of Medicine, Chiba University, Japan.
Abstract:
Migration of medial smooth muscle cells (SMC) into the intima is important in intimal thickening of atherosclerotic tissues. To study the functions of three isoforms of platelet-derived growth factor (PDGF) in atherosclerosis, we investigated their effects on SMC migration by Boyden's chamber method. Although PDGF-AB and PDGF-BB enhanced SMC migration dose-dependently, PDGF-AA did not enhance SMC migration, but instead inhibited SMC migration induced by PDGF-AB or PDGF-BB. PDGF-AA also inhibited SMC migration induced by two other migration factors, fibronectin and SMC-derived migration factor. PDGF-AA is considered to be coexpressed with transforming growth factor (TGF)-beta 1 in atherosclerotic tissues. Treatment of SMC with TGF-beta 1 reduced an autocrine migration activity from SMC. Studies using anti-PDGF antibody revealed that an increased secretion of PDGF-AA by TGF-beta 1 caused the reduced migration activity. cAMP increase by forskolin and dibutyryl cAMP suppressed SMC migration, whereas cAMP decrease by pertussis toxin had no effects on PDGF-AA-suppressed migration. In contrast, staurosporine, an inhibitor of protein kinase C, enhanced SMC migration and neutralized the inhibitory effect of PDGF-AA. These findings suggest that PDGF-AA regulates SMC migration in intimal thickening in atheroma formation and that protein kinase C may play an important role in the inhibitory mechanism of PDGF-AA.
Insights
Platelet-derived growth factor AA (PDGF-AA) inhibits smooth muscle cell migration, a key process in atherosclerosis development. Protein kinase C activation is involved in this inhibitory mechanism, suggesting a novel therapeutic target for intimal thickening.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Atherosclerosis Research
Background:
- Smooth muscle cell (SMC) migration into the intima is crucial for intimal thickening in atherosclerotic tissues.
- Platelet-derived growth factor (PDGF) isoforms play significant roles in vascular diseases.
Purpose of the Study:
- To investigate the differential effects of PDGF isoforms (PDGF-AA, PDGF-AB, PDGF-BB) on SMC migration.
- To elucidate the role of PDGF-AA in SMC migration and its interaction with other signaling pathways.
Main Methods:
- Boyden's chamber assay was used to assess SMC migration.
- Experiments involved various PDGF isoforms, fibronectin, SMC-derived migration factor, transforming growth factor-beta 1 (TGF-beta 1), forskolin, dibutyryl cAMP, pertussis toxin, and staurosporine.
Main Results:
- PDGF-AB and PDGF-BB dose-dependently enhanced SMC migration.
- PDGF-AA inhibited SMC migration induced by PDGF-AB, PDGF-BB, fibronectin, and SMC-derived migration factor.
- TGF-beta 1 treatment reduced SMC autocrine migration activity, linked to increased PDGF-AA secretion.
- Protein kinase C inhibition (staurosporine) enhanced SMC migration and counteracted PDGF-AA's inhibitory effect.
Conclusions:
- PDGF-AA plays a regulatory role in SMC migration during intimal thickening in atheroma formation.
- Protein kinase C activation appears to be a key component of the inhibitory mechanism mediated by PDGF-AA.