Objective-G␣ 12/13 play a role in oncogenic transformation and tumor growth. Cysteine-rich protein 61 (CYR61) is a growth-factor-inducible angiogenic factor. In view of potential overlapping functions between G␣ 12/13 and CYR61, this study investigated the role of these G proteins in CYR61 induction in association with hyperplastic vascular abnormality. Methods and Results-Overexpression of activated G␣ 12 or G␣ 13 induced CYR61 expression in vascular smooth muscle cells (VSMCs). Gene knockdown and knockout experiments revealed that sphingosine-1-phosphate (S1P) treatment induced CYR61 via G␣ 12/13 . JunD/activator protein-1 (AP-1) was identified as a transcription factor required for CYR61 transactivation by S1P. Deficiencies in G␣ 12/13 abrogated AP-1 activation and AP-1-mediated CYR61 induction. c-Jun N-terminal kinase was responsible for CYR61 induction. Moreover, deficiencies of G␣ 12/13 abolished c-Jun N-terminal kinase-dependent CYR61 induction by S1P. N-acetyl-L-cysteine or NADPH oxidase inhibitor treatment reversed CYR61 induction by S1P, indicating that reactive oxygen species are responsible for this process. The levels of G␣ 12/13 were increased within thickened intimas and medias in wire-injured mouse femoral arteries, which was accompanied by simultaneous CYR61 induction. Moreover, G␣ 12/13 and CYR61 were costained in the arteriosclerotic lesions immediately adjacent to human tumor tissues. Key Words: atherosclerosis Ⅲ G proteins Ⅲ oncogenes Ⅲ signal transduction Ⅲ vascular biology Ⅲ G␣ 12/13 Ⅲ cysteine-rich protein 61 Ⅲ sphingosine-1-phosphate Ⅲ vascular smooth muscle cell V ascular proliferative disorder and cancer share common aspects in disease development and progression: both are characterized by dysregulation of cell growth and differentiation, oxidative stress, inflammation, and angiogenesis. [1][2][3] In response to vascular injury, vascular smooth muscle cells (VSMCs) migrate toward the intima and abnormally proliferate, leading to neointimal hyperplasia. Exaggerated intimal thickening that occurs with neovascularization then aggravates vascular occlusion and consequently amplifies oxidative stress and inflammatory processes, which may favor tumor growth and dissemination. 3 Moreover, previous clinical reports showed high occurrences of arteriosclerosis in the vicinity of several different tumor tissues. 4,5 However, the underlying molecular basis has not been clarified.
Conclusion-G␣Hyperplastic proliferation of VSMCs results from the stimulation by various growth factors, G-protein-coupled receptor (GPCR) ligands, or inflammatory cytokines, the levels of which are increased in tumor microenvironment. Of the major targets associated with neointimal hyperplasia, the cysteine-rich protein 61 (CYR61, a member of connective tissue growth factor/ cysteine-rich 61/nephroblastoma overexpressed [CCN] family), secreted as an extracellular matrix-associated protein, exerts its downstream signaling by binding to various types of integrins in an autocrine or paracrine manner 6 and thus modulates the...
