CYR61 (CCN1) Is Essential for Placental Development and Vascular Integrity
Open accessAbstract
CYR61 (CCN1) is a member of the CCN family of secreted matricellular proteins that includes connective tissue growth factor (CCN2), NOV (CCN3), WISP-1 (CCN4), WISP-2 (CCN5), and WISP-3 (CCN6). First identified as the product of a growth factor-inducible immediate-early gene, CYR61 is an extracellular matrix-associated angiogenic inducer that functions as a ligand of integrin receptors to promote cell adhesion, migration, and proliferation. Aberrant expression of Cyr61 is associated with breast cancer, wound healing, and vascular diseases such as atherosclerosis and restenosis. To understand the functions of CYR61 during development, we have disrupted the Cyr61 gene in mice. We show here that Cyr61-null mice suffer embryonic death: approximately 30% succumbed to a failure in chorioallantoic fusion, and the reminder perished due to placental vascular insufficiency and compromised vessel integrity. These findings establish CYR61 as a novel and essential regulator of vascular development. CYR61 deficiency results in a specific defect in vessel bifurcation (nonsprouting angiogenesis) at the chorioallantoic junction, leading to an undervascularization of the placenta without affecting differentiation of the labyrinthine syncytiotrophoblasts. This unique phenotype is correlated with impaired Vegf-C expression in the allantoic mesoderm, suggesting that CYR61-regulated expression of Vegf-C plays a role in vessel bifurcation. The genetic and molecular basis of vessel bifurcation is presently unknown, and these findings provide new insight into this aspect of angiogenesis.
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CCN1 is required for cardiovascular development in embryos.
“plays essential roles in cardiovascular development during embryogenesis”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
Ccn1-null mice are defective in placental vessel bifurcation and suffer severe cardiovascular defects.
“Consistent with an important role for CCN1 in angiogenesis in vivo, Ccn1-null mice are defective in placental vessel bifurcation and suffer severe cardiovascular defects [85,86].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
CCN1 can regulate expression of angiogenic factors such as VEGF-A and VEGF-C.
“In addition to its direct effects on endothelial cells, CCN1 can also regulate the expression of angiogenic factors such as VEGF-A and VEGF-C [85,87].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
Despite normal vasculogenesis in Ccn1-null mice, specific angiogenic defects occur: vessel bifurcation is impaired in the chorionic plate, resulting in few sprouting vessels penetrating the labyrinth and an undervascularized placenta.
“Despite normal vasculogenesis in Ccn1-null mice, specific angiogenic defects are observed. Vessel bifurcation is impaired in the chorionic plate of Ccn1-null embryos, resulting in a dearth of sprouting vessels that penetrate into the labyrinth, and thus an undervascularized placenta [85].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
Trophoblast differentiation and syncytiotrophoblast formation at the chorionic plate occur normally in the Ccn1-null placenta, forming the trilaminar trophoblast barrier; therefore the labyrinthine vascular deficiency in Ccn1-null mice is not due to trophoblast defects.
“However, trophoblast differentiation and syncytiotrophoblast formation at the chorionic plate occur normally in the Ccn1-null placenta, forming the trilaminar trophoblast barrier between fetal vessels and maternal blood sinuses where fetal vessels are found. Therefore, the labyrinthine vascular deficiency in Ccn1-null mice is not due to trophoblast defects.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
Ccn1 expression during mouse embryogenesis is tightly associated with development of skeletal, cardiovascular, and neuronal systems, and targeted disruption of Ccn1 in mice results in embryonic lethality.
“Ccn1 expression during mouse embryogenesis is tightly associated with development of the skeletal, cardiovascular, and neuronal systems [82], and targeted disruption of Ccn1 in mice results in embryonic lethality.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
Although Ccn1 is prominently expressed in the skeletal system during embryogenesis, Ccn1-null mice succumb too early in development for its role in skeletal development to be assessed fully.
“Although Ccn1 is prominently expressed in the skeletal system during embryogenesis [82], Ccn1-null mice succumb too early in development for its role in skeletal development to be assessed fully [85].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
Approximately 30% of Ccn1-null embryos fail to form chorioallantoic fusion at E8.5 and die by E9.5, whereas the remaining embryos perish at mid-gestation from placental vascular insufficiency, loss of embryonic vascular integrity, hemorrhage, and severe AVSD.
“Approximately 30% of Ccn1-null embryos fail to form chorioallantoic fusion at E8.5 and die by E9.5, whereas the remaining embryos perish at mid-gestation from placental vascular insufficiency, loss of embryonic vascular integrity, hemorrhage, and severe cardiac atrioventricular septal defect (AVSD) [85,86].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [85]
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Self-citationA coding RNA segment that enhances the ribosomal recruitment of chicken <i>ccn1</i> mRNA
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- Authors
- Mo, F.-E., Muntean, A. G., Chen, C.-C., Stolz, D. B., Watkins, S. C., & Lau, L. F.
- Affiliations
- University of Illinois Chicago (US)
- University of Pittsburgh (US)
- Corresponding author
- Lau, Lester F.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2002-12-01
- Volume
- 22
- Issue
- 24
- Pages
- 8709-8720
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC139880
- OpenAlex
- W1974307668
- Cited by
- 416
- References
- 52
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 6 · 2023: 17 · 2022: 9 · 2021: 13 · 2020: 12 · 2019: 15 · 2018: 8 · 2017: 11 · 2016: 27 · 2015: 31 · 2014: 23 · 2013: 20 · 2012: 17
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA76541)
- National Cancer Institute (CA 76541, R01CA046565, R01CA076541, R29CA076541, CA-46565)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- CYR61, CCN family, placental development, vessel bifurcation, VEGF-C, syncytiotrophoblast, embryonic lethality, matricellular proteins, integrin ligands, angiogenesis
- MeSH terms
- Animals, Blood Vessels, Cell Differentiation, Embryo, Mammalian, Genotype, Humans, Neovascularization, Pathologic, Placenta, Placentation, Endothelial Growth Factors, Immediate-Early Proteins, Mice, Knockout, Gene Targeting, Neovascularization, Physiologic, Platelet Endothelial Cell Adhesion Molecule-1, In Situ Nick-End Labeling, Intercellular Signaling Peptides and Proteins, Vascular Endothelial Growth Factor C, Mice, Cysteine-Rich Protein 61
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