Expression of CYR61, an Angiogenic Immediate Early Gene, in Arteriosclerosis and Its Regulation by Angiotensin II

Abstract

Background-The renin-angiotensin system is thought to be involved in development and progression of arteriosclerosis, thereby contributing to adverse cardiovascular events. To elucidate the role of angiotensin II (Ang II) at a cellular level, we analyzed the Ang II-induced gene expression profile. Methods and Results-Genes induced on Ang II stimulation (10 Ϫ7 mol/L, 45 minutes) in rat smooth muscle cells were analyzed by polymerase chain reaction selected subtraction. In addition to known genes, such as interleukin 6, leukemia inhibitory factor, and c-fos, we identified CYR61, an angiogenic immediate early gene. Northern blot analysis revealed a rapid 2.5-fold increase of CYR61 transcript levels by Ang II, peaking at 30 minutes, which was blunted by Ang II type 1 receptor blockade. Exposure of rat aortic rings to Ang II (30 minutes) revealed a 2-fold, and intraperitoneal injection of Ang II (30 minutes) in mice a 3-fold, increase of aortic CYR61 transcripts. In arteriosclerotic aortas of apolipoprotein E-deficient mice, CYR61 transcripts confirmed by in situ hybridization and proteins shown by immunohistochemistry were elevated, whereas they were hardly detectable in wild types. In human carotid atherectomies and arteriosclerotic coronary arteries, immunohistochemical analysis revealed expression of CYR61 within connective tissue in neointima, adventitia, and surrounding small capillaries and blood vessels, colocalized with ACE and Ang II. Normal human arteries showed no significant staining for CYR61. Conclusions-CYR61, an angiogenic factor, is induced by Ang II in vascular cells and tissue. The expression of CYR61, colocalized with Ang II and ACE, in small vessels of human arteriosclerotic lesions is consistent with the notion that the activated renin-angiotensin system may contribute to plaque neovascularization by enhancing regulators of microvessel formation and cell proliferation.

Angiogenic Protein Cyr61 is Expressed by Podocytes in Anti-Thy-1 Glomerulonephritis

“…Previous reports showed that Cyr61 is expressed in endothelial and smooth muscle cells in the developing mouse blood vessels (34,35) but only weakly in vessels of normal adult mice and humans (36). In the present study, Cyr61 was expressed in normal afferent and efferent arterioles, in which Cyr61 expression might be upregulated by strong mechanical stretch due to shear stress (37).…”

Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress

“…In addition, it has been shown that angiotensin II infusion into hyperlipidemic mice augments lesion formation independently of elevations in blood pressure by eliciting a Th1 response 25 or by increasing the angiogenic properties of the plaque. 26 Despite the multipotent ability of angiotensin II to affect plaque vulnerability, our data show that intraplaque hemorrhages occurred in the lowered shear stress lesions only in response to angiotensin II stimulation.…”

Integrin αDβ2, an adhesion receptor up-regulated on macrophage foam cells, exhibits multiligand-binding properties

“…These included: (1) the ECM proteins fibronectin, vitronectin, and fibrinogen, and (2) the proteins Cyr61 and plasminogen, which are overexpressed or become ECM-associated during the inflammatory responses. 22,23 Furthermore, cell adhesion to VCAM-1 was tested because it represents an established ␣ D ␤ 2 ligand. 1 Additionally, cell adhesion to the fibrinogen P2-C peptide, which duplicates the binding site for ␣ M ␤ 2 in fibrinogen 24 and contains the generic recognition information required for ␣ M ␤ 2 binding, 25 was examined.…”