The Angiogenic Factor Cysteine-Rich 61 (CYR61, CCN1) Supports Vascular Smooth Muscle Cell Adhesion and Stimulates Chemotaxis through Integrin 6 1 and Cell Surface Heparan Sulfate Proteoglycans
Abstract
Cysteine-rich 61 (CYR61, CCN1) is a heparin-binding, extracellular, matrix-associated protein of the cysteine-rich 61/nephroblastoma family, which also includes connective tissue growth factor, nephroblastoma overexpressed, Wnt-induced secreted protein-1 (WISP-1), WISP-2, and WISP-3. CYR61 induces angiogenesis in vivo and supports cell adhesion, promotes cell migration, and enhances growth factor-stimulated mitogenesis in fibroblasts and endothelial cells. Although the expression of CYR61 has been observed in arterial walls, its function in vascular smooth muscle cells (VSMCs) has not been examined to date. Here we show that purified CYR61 supports VSMC adhesion in a dose-dependent, saturable manner through integrin α6β1 with an absolute requirement of cell surface heparan sulfate proteoglycans. In addition, CYR61 induces VSMC chemotaxis, but not chemokinesis, through integrin α6β1 and heparan sulfate proteoglycans. Heparin-binding defective CYR61 mutants are unable to support VSMC adhesion but can still induce chemotaxis at a reduced level. Following balloon angioplasty in rat carotid artery, CYR61 protein level is elevated in the media and neointima of the injured vessel by d 4 post angioplasty, peaks from d 7 to 14, and remains high for at least 28 d. These data demonstrate the activities of CYR61 in VSMCs, identify the receptors that mediate its functions, and show that CYR61 is synthesized in arterial smooth muscle walls during proliferative restenosis. Together, these results implicate CYR61 as a novel factor that modulates the responses of VSMCs to vascular injury.
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CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells, αIIbβ3 in activated platelets, αMβ2 in monocytes and macrophages, and αDβ2 in macrophage foam cells.
“Subsequent studies have shown that CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells [55,56], αIIbβ3 in activated platelets [57], αMβ2 in monocytes and macrophages [58,59], and αDβ2 in macrophage foam cells [60].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [56]
CCN1 stimulates cell migration in fibroblasts, smooth muscle cells, endothelial cells, and certain cancer cells.
“Furthermore, CCN1 stimulates cell migration in fibroblasts, smooth muscle cells and endothelial cells [56,71,72], and certain cancer cells [73–75].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [56]
CCN1 expression is elevated in vascular injury.
“In addition to cutaneous wound healing, CCN1 expression is elevated in remodeling cardiomyocytes after myocardial infarctions [24], in vascular injury [56], and in the long bones during fracture repair, notably in proliferating chondrocytes and osteoblasts [127,128].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [56]
CCN1 is overexpressed in vascular smooth muscle cells of atherosclerotic lesions and in the neointima of restenosis after balloon angioplasty, in rodent models and humans.
“CCN1 is overexpressed in vascular smooth muscle cells of atherosclerotic lesions and in the neointima of restenosis after balloon angioplasty, both in rodent models and in humans [23,56,58,135].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [56]
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- Authors
- Grzeszkiewicz, T. M.
- Affiliations
- University of Illinois Chicago (US)
- Corresponding author
- Grzeszkiewicz, T. M.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2002-04-01
- Volume
- 143
- Issue
- 4
- Pages
- 1441-1450
- ISSN
- 0013-7227 (ISSN-L)
- OpenAlex
- W4236222382
- Cited by
- 23
- References
- 3
- Citations by year
- 2025: 1 · 2023: 1 · 2012: 1
- FWCI
- 0.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
- Keywords
- CYR61, vascular smooth muscle cells, alpha6beta1 integrin, heparan sulfate proteoglycans, cell adhesion, chemotaxis, angiogenesis, balloon angioplasty, restenosis, neointima, vascular injury, heparin binding, extracellular matrix proteins
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