A CTGF-YAP Regulatory Pathway is Essential for Angiogenesis and Barriergenesis in the Retina

Moon, Sohyun; Lee, Sangmi; Caesar, JoAnn; Pruchenko, Sarah; Leask, A; Knowles, James A.; Sinon, Jose; Chaqour, Brahim

doi:10.2139/ssrn.3569537

Cited by 6 publications

(14 citation statements)

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“…Other defects included impaired growth plate angiogenesis with formation of fewer intact capillaries, and disrupted organization of large blood vessels. Our recent studies revealed retinal hypovascularization and altered vascular permeability resulting from EC-specific loss of CCN2/CTGF [50]. CCN2/CTGF depletion perturbed genes and pathways that regulate proliferation, migration, and junction formation in ECs.…”

Section: Constitutive and Inducible Ccn2/ctgf Knockout Phenotypementioning

confidence: 87%

“…Müller cells are also a major source of ECM proteins in the retina. As shown in our recent work, the Müller cell secretome includes the matricellular protein CCN2/CTGF, which plays a major role in vessel development and barrier integrity, although the precise function of Müller cell-derived CCN2/CTGF remains to be determined [50].…”

Section: Blood Vessel Development and Organization In The Retinamentioning

confidence: 95%

“…In the healthy human eye, CCN2/CTGF is found in the vascular ECs of the iris, ciliary body, choroid, choriocapillaris, and the central retinal artery [90]. Using a transgenic GFP reporter mouse as a proxy for CCN2/CTGF expression, we have detected CCN2/CTGF:GFP signal at relatively high levels in the vasculature of the retina (in the superficial vascular plexus around the optic nerve head, and intermediate and deep capillary plexuses within the inner nuclear layer), choriocapillaris, the corneal endothelium and lens subcapsular epithelium [50]. ECs, mural cells (e.g., smooth muscle cells, pericytes), Müller cells, and retinal pigment epithelial cells (RPE) cells are major producers of CCN2/CTGF in retina of new born and adult mice while other cells such as astrocytes and microglia do not appear to be an important source of CCN2/CTGF [91].…”

Section: Ccn2/ctgf Expression During Embryonic and Fetal Tissue Developmentmentioning

confidence: 96%

“…CCN2/CTGF has tightly regulated expression patterns and exhibit ECM-like structural features and growth factor-like activities including modulation of cell motility, adhesion, proliferation, survival, ECM protein expression and reprogramming of gene expression [34,[78][79][80]. As such, this molecule plays a critical role in blood vessel formation and regeneration [27,34,50,81].…”

Section: Ccn2/ctgf Structure and Functionmentioning

confidence: 99%

“…Furthermore, several ECM proteins were downregulated, including laminin 4, SPARC, tenascin C, FACIT collagens, and proteoglycans. Many of these are critical for vascular BM integrity [50]. Thus, CCN2/CTGF signaling potentially contributes to the regulation of the vascular matrix composition and mechanical properties [27].…”

Section: Constitutive and Inducible Ccn2/ctgf Knockout Phenotypementioning

confidence: 99%

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Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function

Chaqour

Karrasch

2020

IJMS

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The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or properties, and the ensuing changes in vascular compliance affect vasodilator responses, microvascular pressure transmission, and collateral perfusion. The changes in microvascular compliance are independent factors initiating, driving, and/or exacerbating a plethora of microvascular diseases of the eye including diabetic retinopathy (DR) and vitreoretinopathy, retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and neovascular glaucoma. Congruently, one of the major challenges with most vascular regenerative therapies utilizing localized growth factor, endothelial progenitor, or genetically engineered cell delivery, is the regeneration of blood vessels with physiological compliance properties. Interestingly, vascular cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins and the actomyosin cytoskeleton, which generates biochemical signals that culminate in a rapid expression of matricellular proteins such as cellular communication network 1 (CCN1) and CCN2 (aka connective tissue growth factor or CTGF). Loss or gain of function of these proteins alters genetic programs of cell growth, ECM biosynthesis, and intercellular signaling, that culminate in changes in cell behavior, polarization, and barrier function. In particular, the function of the matricellular protein CCN2/CTGF is critical during retinal vessel development and regeneration wherein new blood vessels form and invest a preformed avascular neural retina following putative gradients of matrix stiffness. These observations underscore the need for further in-depth characterization of the ECM-derived cues that dictate structural and functional properties of the microvasculature, along with the development of new therapeutic strategies addressing the ECM-dependent regulation of pathophysiological stiffening of blood vessels in ischemic retinopathies.

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Section: Constitutive and Inducible Ccn2/ctgf Knockout Phenotypementioning

confidence: 87%

Section: Blood Vessel Development and Organization In The Retinamentioning

confidence: 95%

Section: Ccn2/ctgf Expression During Embryonic and Fetal Tissue Developmentmentioning

confidence: 96%

Section: Ccn2/ctgf Structure and Functionmentioning

confidence: 99%

Section: Constitutive and Inducible Ccn2/ctgf Knockout Phenotypementioning

confidence: 99%

See 3 more Smart Citations

Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function

Chaqour

Karrasch

2020

IJMS

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Et tu, CCN1….

Leask

2020

J. Cell Commun. Signal.

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The CCN family of matricellular proteins are recognized bona fide targets for therapeutically targeting so-called chronic inflammatory diseases, including fibrosis and cancers. The majority of the work supporting this contention has been derived from examining CCN2, formerly, and unhelpfully, termed "connective tissue growth factor." Both CCN2, and its related protein, CCN1, formerly termed "cysteine-rich protein 61", are positively regulated by not only TGFbeta, but also by the hippo/YAP/ TAZ mechanotransduction pathway that appears to drive these pathologies. Indeed, increasing evidence indicates that CCN1 also contributes to these fibrosis and cancers and, consequently, targeting both CCN2 and CCN1 simultaneously could be of therapeutic value. This commentary focuses on a recent, exciting paper (Ju et al., 2020, Scientific Reports, 10, 3201) suggesting that CCN1 is a target for non-alcoholic steatohepatitis (NASH).Keywords CCN1 . Cyr61 . CCN family . NASH . Non-alcoholic steatohepatitis . Fibrosis . Steatosis . Matricellular proteins Non-alcoholic fatty liver disease (NAFLD), a liver disease affecting people who drink little to no alcohol, is characterized by the excessive storage of fat in liver cells. NAFLD is the most common liver disease in Canada affecting about 20% of Canadians. The most common cause of NAFLD is obesity. Certain conditions that often accompany and may contribute to fatty liver disease include: diabetes mellitus, hyperlipidemia, insulin resistance and high blood pressure.Non-alcoholic steatohepatitis (NASH), a serious form of NAFLD, is characterized by liver fibrosis and cirrhosis. In most cases, NASH seems to be a slowly progressive disease. However, NASH patients can have liver cancer or liver failure and an increased risk of cardiovascular disease and diabetes. Inflammation in the liver plays a critical role in the development of NASH, and NASH-associated liver fibrosis. However, the underlying mechanisms have not been completely elucidated.The CCN family, including CCN1 [cysteine-rich protein 61 (Cyr61)], CCN2 (connective tissue growth factor), and CCN3 (nephroblastoma overexpressed), are matricellular proteins that play critical roles in development, differentiation,

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Rab40c Regulates Focal Adhesions and Protein Phosphatase 6 Activity by Controlling ANKRD28 Ubiquitylation and Degradation

Han

Prekeris

2021

Preprint

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Rab40c is a SOCS box containing protein which binds Cullin5 to form a ubiquitin E3 ligase complex (Rab40c/CRL5) to regulate protein ubiquitylation. However, the exact functions of Rab40c remain to be determined, and what proteins are the targets of Rab40c-Cullin5 mediated ubiquitylation in mammalian cells are unknown. Here we showed that in migrating MDA-MB-231 cells Rab40c regulates focal adhesion number, size, and distribution. Mechanistically, we found that Rab40c binds the protein phosphatase 6 complex and ubiquitylates one of its subunits, ANKRD28, thus, leading to its lysosomal degradation. Furthermore, we identified that phosphorylation of FAK and MOB1 is decreased in Rab40c knockout cells, which may contribute to focal adhesion site regulation by Rab40c. Thus, we propose a model where Rab40c/CRL5 regulates ANKRD28 ubiquitylation and degradation, leading to a decrease in PP6 activity, which ultimately affects FAK and Hippo pathway signaling to alter focal adhesion dynamics.

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A CTGF-YAP Regulatory Pathway is Essential for Angiogenesis and Barriergenesis in the Retina

Cited by 6 publications

References 0 publications

Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function

Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function

Et tu, CCN1….

Rab40c Regulates Focal Adhesions and Protein Phosphatase 6 Activity by Controlling ANKRD28 Ubiquitylation and Degradation

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