CD36 Enhances Vascular Smooth Muscle Cell Proliferation and Development of Neointimal Hyperplasia

Abstract

Objective— Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results— We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress–induced intima thickening models, we compared neointimal hyperplasia in Apoe −/− , Cd36 −/− /Apoe −/− , and CD36 specifically deleted in VSMC (VSMC cd36 −/− ) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36 −/− /Apoe −/− compared with Apoe −/− mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36 −/− mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36 −/− VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36 −/− VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36 −/− VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-β1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle α actin, and dramatically increased cell contraction. Conclusions— CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.

Distribution and Dynamic Changes in Matrix Metalloproteinase (MMP)-2, MMP-9, and Collagen in an In Stent Restenosis Process

“…Both MMP-2 and MMP-9 can activate VSMCs to promote the production of new collagen. 15,16 The study showed that in neointima MMP-2 and MMP-9 were positively correlated with the amount of new collagen during the neointimal regression period. This suggests that the reduction of MMP-2 and MMP-9 in neointima might, in part, contribute to the decrease in the amount of new collagen during this period.…”

“…12,14 This partly explains this chronological sequence. MMP-2 and MMP-9 can activate VSMCs to proliferate and express collagen, 15,16 and the collagen accumulation phase was more prolonged than the VSMC proliferation phase, 17 so the accumulation of collagen reached a maximum even if the expression of MMP-2 and MMP-9 was low at 56 days. In this study, the changing trend of MMP-2 and MMP-9 is consistent with a previous study.…”

Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives

“…Furthermore, activated platelets internalize oxLDL, while platelets loaded with oxLDL further activate the endothelium, release chemokines to recruit monocytes, and promote foam cell development [ 38 ]. CD36 deficiency in ApoE −/− mice can inhibit neointimal hyperplasia and vascular smooth muscle cells (VSMCs) proliferation, which may prevent atherosclerosis and restenosis [ 39 ]. Lectin-like oxidized LDL receptor 1 (LOX-1) was identified as another major receptor of oxLDL in human platelets [ 40 ].…”

Role of the signal transducer and activator of transcription 3 protein in the proliferation of vascular smooth muscle cells

“…71 CD36 promotes VSMC proliferation via the upregulation of cyclin A expression and increases dedifferentiated VSMC phenotypes via the inhibition of STAT 3 activity. 72…”