Differential effects of platelet-derived growth factor isotypes on human smooth muscle cell proliferation and migration are mediated by distinct signaling pathways.
BACKGROUND
Platelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for vascular smooth muscle cells (SMCs). Three isotypes of PDGF (BB, AB, and AA) have been identified; each of these isotypes may have differing effects on the behaviour of vascular SMCs. In this study we evaluated the influence of PDGF isotypes on proliferation and migration of human venous SMCs and explored the signaling pathways through which these effects are mediated.


METHODS
Proliferation was measured by a 72-hour assay of cell number, and migration was evaluated by a 4-hour microchemotaxis assay. The effects of PDGF isotypes on the activities of the signaling proteins mitogen-activated protein kinase (MAP-K), p 125 focal adhesion kinase (p125FAK), and tensin were measured by immunoprecipitation of these proteins and subsequent phosphorylation on myelin basic protein (in MAP-K) and Western blotting with antiphosphotyrosine (in tensin and p125FAK).


RESULTS
All three isotypes stimulated SMC proliferation (PDGF-BB > AB > AA). PDGF-BB and -AB, but not -AA, stimulated chemotaxis. All three isotypes activated MAP-K with an intensity that corresponded to their proliferative effects. PDGF-BB and -AB tyrosine phosphorylated tensin and p125FAK, whereas PDGF-AA had no effect on either of these proteins.


CONCLUSIONS
For human vascular SMCs the physiologic effects and the signaling pathways that mediate these effects are specific for each of the three PDGF isotypes. These data also suggest an association between MAP-K and SMC proliferation and between the proteins, p125FAK and tensin, and migration.
Jiang
B
B
Department of Surgery, Beth Israel Hospital, Harvard Medical School, Boston, Mass 02215, USA.
Yamamura
S
S
Nelson
P R
PR
Mureebe
L
L
Kent
K C
KC
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D007536:Isomerism; D008840:Microfilament Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000070876:Tensins; D014443:Tyrosine / Q000378:metabolism
D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010982:Platelet-Derived Growth Factor; D000070876:Tensins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017871:Calcium-Calmodulin-Dependent Protein Kinases