Novel Paracrine Functions of Smooth Muscle Cells in Supporting Endothelial Regeneration Following Arterial Injury
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:124 |
|---|---|
| Enthalten in: |
Circulation research - 124(2019), 8 vom: 12. Apr., Seite 1253-1265 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Ren, Jun [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 23.01.2020 Date Revised 12.04.2020 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1161/CIRCRESAHA.118.314567 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM293654581 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM293654581 | ||
| 003 | DE-627 | ||
| 005 | 20231225075803.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1161/CIRCRESAHA.118.314567 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0978.xml |
| 035 | |a (DE-627)NLM293654581 | ||
| 035 | |a (NLM)30739581 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Ren, Jun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Novel Paracrine Functions of Smooth Muscle Cells in Supporting Endothelial Regeneration Following Arterial Injury |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.01.2020 | ||
| 500 | |a Date Revised 12.04.2020 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a OBJECTIVE: To test whether PKCδ-mediated paracrine functions of SMCs influence reendothelialization in rodent models of arterial injury | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: SMCs promote reendothelialization in a PKCδ-dependent paracrine mechanism, likely through CXCL7-mediated recruitment of endothelial cells from uninjured endothelium | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a STAT3 transcription factor | |
| 650 | 4 | |a chemokines, CXC | |
| 650 | 4 | |a endothelial cells | |
| 650 | 4 | |a muscle, smooth | |
| 650 | 4 | |a protein kinase C-delta | |
| 650 | 4 | |a regeneration | |
| 650 | 7 | |a Chemokine CXCL1 |2 NLM | |
| 650 | 7 | |a Chemokines |2 NLM | |
| 650 | 7 | |a Chemokines, CXC |2 NLM | |
| 650 | 7 | |a Cxcl1 protein, rat |2 NLM | |
| 650 | 7 | |a Cxcr2 protein, rat |2 NLM | |
| 650 | 7 | |a Ppbp protein, rat |2 NLM | |
| 650 | 7 | |a Receptors, Interleukin-8B |2 NLM | |
| 650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
| 650 | 7 | |a Stat3 protein, rat |2 NLM | |
| 650 | 7 | |a Protein Kinase C-delta |2 NLM | |
| 650 | 7 | |a EC 2.7.11.13 |2 NLM | |
| 700 | 1 | |a Zhou, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a Pilli, Vijaya Satish Sekhar |e verfasserin |4 aut | |
| 700 | 1 | |a Phan, Noel |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qiwei |e verfasserin |4 aut | |
| 700 | 1 | |a Gupta, Kartik |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhenjie |e verfasserin |4 aut | |
| 700 | 1 | |a Sheibani, Nader |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Bo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Circulation research |d 1953 |g 124(2019), 8 vom: 12. Apr., Seite 1253-1265 |w (DE-627)NLM000001910 |x 1524-4571 |7 nnns |
| 773 | 1 | 8 | |g volume:124 |g year:2019 |g number:8 |g day:12 |g month:04 |g pages:1253-1265 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1161/CIRCRESAHA.118.314567 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 124 |j 2019 |e 8 |b 12 |c 04 |h 1253-1265 | ||