CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration.
OBJECTIVE
CCN3 belongs to the CCN family, which constitutes multifunctional secreted proteins that act as matrix cellular regulators. We investigated the pathophysiological roles of CCN3 in the vessels.


RESULTS
We examined the effects of CCN3 on the proliferation and migration of rat vascular smooth muscle cells (VSMC). CCN3 knockout mice were created, and vascular phenotypes and neointimal hyperplasia induced by photochemically induced thrombosis were investigated. CCN3 suppressed the VSMC proliferation induced by fetal bovine serum. The neutralizing antibody for transforming growth factor-beta did not affect the growth inhibitory effect of CCN3. Moreover, CCN3 enhanced the mRNA expression of cyclin-dependent kinase inhibitors, p21 and p15. Gamma secretase inhibitor, an inhibitor of Notch signaling, partially inhibited the enhanced expression of p21 induced by CCN3. CCN3 also inhibited the VSMC migration. Finally, the histopathologic evaluation of the arteries 21 days after the endothelial injury revealed a 6-fold enhancement of neointimal thickening in the null mice compared with the wild-type mice.


CONCLUSIONS
CCN3 suppresses neointimal thickening through the inhibition of VSMC migration and proliferation. Our findings indicate the involvement of CCN3 in vascular homeostasis, especially on injury, and the potential usefulness of this molecule in the modulation of atherosclerotic vascular disease.
Shimoyama
Tatsushi
T
Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Hiraoka
Shûichi
S
Takemoto
Minoru
M
Koshizaka
Masaya
M
Tokuyama
Hirotake
H
Tokuyama
Takahiko
T
Watanabe
Aki
A
Fujimoto
Masaki
M
Kawamura
Harukiyo
H
Sato
Seiya
S
Tsurutani
Yuya
Y
Saito
Yasushi
Y
Perbal
Bernard
B
Koseki
Haruhiko
H
Yokote
Koutaro
K
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D055514:Nephroblastoma Overexpressed Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism
C526319:CCN3 protein, human; C493958:Cdkn1a protein, rat; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D055514:Nephroblastoma Overexpressed Protein; D011480:Protease Inhibitors; D051880:Receptors, Notch; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D053829:Amyloid Precursor Protein Secretases