Dataset Information

Different modes of endothelial-smooth muscle cell interaction elicit differential ?-catenin phosphorylations and endothelial functions.

ABSTRACT: ?-Catenin phosphorylation plays important roles in modulating its functions, but the effects of different phosphorylated forms of ?-catenin in response to heterocellular interaction are unclear. Here we investigated whether distinct modes of phosphorylation on ?-catenin could be triggered through heterocellular interactions between endothelial cells (ECs) and smooth muscle cells (SMCs), and the consequent modulation of EC functions. ECs were cocultured with SMCs to initiate direct contact and paracrine interaction. EC-SMC coculture induced EC ?-catenin phosphorylations simultaneously at tyrosine 142 (Tyr142) and serine 45/threonine 41 (Ser45/Thr41) at the cytoplasm/nuclei and the membrane, respectively. Treating ECs with SMC-conditional medium induced ?-catenin phosphorylation only at Ser45/Thr41. These findings indicate that different phosphorylation effects of EC-SMC coculture were induced through heterocellular direct contact and paracrine effects, respectively. Using specific blocking peptides, antagonists, and siRNAs, we found that the ?-catenin Tyr142-phosphorylation was mediated by connexin 43/Fer and that the ?-catenin Ser45/Thr41-phosphorylation was mediated by SMC-released bone morphogenetic proteins through VE-cadherin and bone morphogenetic protein receptor-II/Smad5. Transfecting ECs with ?-catenin-Tyr142 or -Ser45 mutants showed that these two phosphorylated forms of ?-catenin modulate differential EC function: The Tyr142-phosphorylated ?-catenin stimulates vascular cell-adhesion molecule-1 expression to increase EC-monocytic adhesion, but the Ser45/Thr41-phosphorylated ?-catenin attenuates VE-cadherin-dependent junction structures to increase EC permeability. Our findings provide new insights into the understanding of regulatory complexities of distinct modes of ?-catenin phosphorylations under EC-SMC interactions and suggest that different phosphorylated forms of ?-catenin play important roles in modulating vascular pathophysiology through different heterocellular interactions.

SUBMITTER: Chang SF

PROVIDER: S-EPMC3918788 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Different modes of endothelial-smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions.

Chang Shun-Fu SF Chen Li-Jing LJ Lee Pei-Ling PL Lee Ding-Yu DY Chien Shu S Chiu Jeng-Jiann JJ

Proceedings of the National Academy of Sciences of the United States of America 20140121 5

β-Catenin phosphorylation plays important roles in modulating its functions, but the effects of different phosphorylated forms of β-catenin in response to heterocellular interaction are unclear. Here we investigated whether distinct modes of phosphorylation on β-catenin could be triggered through heterocellular interactions between endothelial cells (ECs) and smooth muscle cells (SMCs), and the consequent modulation of EC functions. ECs were cocultured with SMCs to initiate direct contact and pa ...[more]

PMID: 24449884

Similar Datasets

Project description:RATIONALE:Regeneration of denuded or injured endothelium is an important component of vascular injury response. Cell-cell communication between endothelial cells and smooth muscle cells (SMCs) plays a critical role not only in vascular homeostasis but also in disease. We have previously demonstrated that PKCδ (protein kinase C-delta) regulates multiple components of vascular injury response including apoptosis of SMCs and production of chemokines, thus is an attractive candidate for a role in SMC-endothelial cells communication. OBJECTIVE:To test whether PKCδ-mediated paracrine functions of SMCs influence reendothelialization in rodent models of arterial injury. METHODS AND RESULTS:Femoral artery wire injury was performed in SMC-conditional Prkcd knockout mice, and carotid angioplasty was conducted in rats receiving transient Prkcd knockdown or overexpression. SMC-specific knockout of Prkcd impaired reendothelialization, reflected by a smaller Evans blue-excluding area in the knockout compared with the wild-type controls. A similar impediment to reendothelialization was observed in rats with SMC-specific knockdown of Prkcd. In contrast, SMC-specific gene transfer of Prkcd accelerated reendothelialization. In vitro, medium conditioned by AdPKCδ-infected SMCs increased endothelial wound closure without affecting their proliferation. A polymerase chain reaction-based array analysis identified Cxcl1 and Cxcl7 among others as PKCδ-mediated chemokines produced by SMCs. Mechanistically, we postulated that PKCδ regulates Cxcl7 expression through STAT3 (signal transducer and activator of transcription 3) as knockdown of STAT3 abolished Cxcl7 expression. The role of CXCL7 in SMC-endothelial cells communication was demonstrated by blocking CXCL7 or its receptor CXCR2, both significantly inhibited endothelial wound closure. Furthermore, insertion of a Cxcl7 cDNA in the lentiviral vector that carries a Prkcd shRNA overcame the adverse effects of Prkcd knockdown on reendothelialization. CONCLUSIONS:SMCs promote reendothelialization in a PKCδ-dependent paracrine mechanism, likely through CXCL7-mediated recruitment of endothelial cells from uninjured endothelium.

Project description:Collaterals are unique blood vessels present in the microcirculation of most tissues that, by cross-connecting a small fraction of the outer branches of adjacent arterial trees, provide alternate routes of perfusion. However, collaterals are especially susceptible to rarefaction caused by aging, other vascular risk factors, and mouse models of Alzheimer's disease-a vulnerability attributed to the disturbed hemodynamic environment in the watershed regions where they reside. We examined the hypothesis that endothelial and smooth muscle cells (ECs and SMCs, respectively) of collaterals have specializations, distinct from those of similarly-sized nearby distal-most arterioles (DMAs) that maintain collateral integrity despite their continuous exposure to low and oscillatory/disturbed shear stress, high wall stress, and low blood oxygen. Examination of mouse brain revealed the following: Unlike the pro-inflammatory cobble-stoned morphology of ECs exposed to low/oscillatory shear stress elsewhere in the vasculature, collateral ECs are aligned with the vessel axis. Primary cilia, which sense shear stress, are present, unexpectedly, on ECs of collaterals and DMAs but are less abundant on collaterals. Unlike DMAs, collaterals are continuously invested with SMCs, have increased expression of Pycard, Ki67, Pdgfb, Angpt2, Dll4, Ephrinb2, and eNOS, and maintain expression of Klf2/4. Collaterals lack tortuosity when first formed during development, but tortuosity becomes evident within days after birth, progresses through middle age, and then declines-results consistent with the concept that collateral wall cells have a higher turnover rate than DMAs that favors proliferative senescence and collateral rarefaction. In conclusion, endothelial and SMCs of collaterals have morphologic and functional differences from those of nearby similarly sized arterioles. Future studies are required to determine if they represent specializations that counterbalance the disturbed hemodynamic, pro-inflammatory, and pro-proliferative environment in which collaterals reside and thus mitigate their risk factor-induced rarefaction.

Dataset Information

Different modes of endothelial-smooth muscle cell interaction elicit differential ?-catenin phosphorylations and endothelial functions.

Publications

Different modes of endothelial-smooth muscle cell interaction elicit differential β-catenin phosphorylations and endothelial functions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets