Limits...
COMP-Ang1 Potentiates EPC Treatment of Ischemic Brain Injury by Enhancing Angiogenesis Through Activating AKT-mTOR Pathway and Promoting Vascular Migration Through Activating Tie2-FAK Pathway.

Moon HE, Byun K, Park HW, Kim JH, Hur J, Park JS, Jun JK, Kim HS, Paek SL, Kim IK, Hwang JH, Kim JW, Kim DG, Sung YC, Koh GY, Song CW, Lee B, Paek SH - Exp Neurobiol (2015)

Bottom Line: COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro.AKT recruited mTOR, SDF-1, and HIF-1α to induce angiogenesis.Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins ανβ3, α4, β1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1α to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

No MeSH data available.


Related in: MedlinePlus

COMP-Ang1 enhances tube formation and migration of hCB-EPCs. (A, C) COMP-Ang1 promoted tube formation, more in EPCs than in HUVECs. COMP-Ang1 (C.A1, 200 ng/mL) was incubated for 24 h (A) followed by densitometric analyses (C). Scale bar, 100 µm. All values are the means±SEM. ****p <0.0001, **p <0.01. (B) COMP-Ang1 promoted the number of EPC incorporated HUVECs. CFSE-labeled EPCs were incorporated on DiI-labeled HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 100 µm. (D, E) COMP-Ang1 promoted cell migration in EPCs better than that in HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 50 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4363334&req=5

Figure 1: COMP-Ang1 enhances tube formation and migration of hCB-EPCs. (A, C) COMP-Ang1 promoted tube formation, more in EPCs than in HUVECs. COMP-Ang1 (C.A1, 200 ng/mL) was incubated for 24 h (A) followed by densitometric analyses (C). Scale bar, 100 µm. All values are the means±SEM. ****p <0.0001, **p <0.01. (B) COMP-Ang1 promoted the number of EPC incorporated HUVECs. CFSE-labeled EPCs were incorporated on DiI-labeled HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 100 µm. (D, E) COMP-Ang1 promoted cell migration in EPCs better than that in HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 50 µm.

Mentions: Because tube formation and cell migration constitute an important process in vessel formation, we tested whether COMP-Ang1 enhances the tube formation and migration of EPCs and HUVECs (Fig. 1A, C). Considerable tube formation occurred when EPCs and HUVEC were incubated on matrigel for 24 h, and COMP-Ang1 significantly increased the tube formation. The greater increase for EPCs in tube formation by COMP-Ang1 was shown than HUVEC.


COMP-Ang1 Potentiates EPC Treatment of Ischemic Brain Injury by Enhancing Angiogenesis Through Activating AKT-mTOR Pathway and Promoting Vascular Migration Through Activating Tie2-FAK Pathway.

Moon HE, Byun K, Park HW, Kim JH, Hur J, Park JS, Jun JK, Kim HS, Paek SL, Kim IK, Hwang JH, Kim JW, Kim DG, Sung YC, Koh GY, Song CW, Lee B, Paek SH - Exp Neurobiol (2015)

COMP-Ang1 enhances tube formation and migration of hCB-EPCs. (A, C) COMP-Ang1 promoted tube formation, more in EPCs than in HUVECs. COMP-Ang1 (C.A1, 200 ng/mL) was incubated for 24 h (A) followed by densitometric analyses (C). Scale bar, 100 µm. All values are the means±SEM. ****p <0.0001, **p <0.01. (B) COMP-Ang1 promoted the number of EPC incorporated HUVECs. CFSE-labeled EPCs were incorporated on DiI-labeled HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 100 µm. (D, E) COMP-Ang1 promoted cell migration in EPCs better than that in HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 50 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363334&req=5

Figure 1: COMP-Ang1 enhances tube formation and migration of hCB-EPCs. (A, C) COMP-Ang1 promoted tube formation, more in EPCs than in HUVECs. COMP-Ang1 (C.A1, 200 ng/mL) was incubated for 24 h (A) followed by densitometric analyses (C). Scale bar, 100 µm. All values are the means±SEM. ****p <0.0001, **p <0.01. (B) COMP-Ang1 promoted the number of EPC incorporated HUVECs. CFSE-labeled EPCs were incorporated on DiI-labeled HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 100 µm. (D, E) COMP-Ang1 promoted cell migration in EPCs better than that in HUVECs. COMP-Ang1 (200 ng/mL) was incubated for 24 h. Scale bar, 50 µm.
Mentions: Because tube formation and cell migration constitute an important process in vessel formation, we tested whether COMP-Ang1 enhances the tube formation and migration of EPCs and HUVECs (Fig. 1A, C). Considerable tube formation occurred when EPCs and HUVEC were incubated on matrigel for 24 h, and COMP-Ang1 significantly increased the tube formation. The greater increase for EPCs in tube formation by COMP-Ang1 was shown than HUVEC.

Bottom Line: COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro.AKT recruited mTOR, SDF-1, and HIF-1α to induce angiogenesis.Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-744, Korea.

ABSTRACT
Successful recovery from brain ischemia is limited due to poor vascularization surrounding the ischemic zone. Cell therapy with strong angiogenic factors could be an effective strategy to rescue the ischemic brain. We investigated whether cartilage oligomeric matrix protein (COMP)-Ang1, a soluble, stable and potent Ang1 variant, enhances the angiogenesis of human cord blood derived endothelial progenitor cells (hCB-EPCs) for rescuing brain from ischemic injury. COMP-Ang1 markedly improved the tube formation of capillaries by EPCs and incorporation of EPCs into tube formation with human umbilical vein endothelial cells (HUVECs) upon incubation on matrigel in vitro. COMP-Ang1 stimulated the migration of EPCs more than HUVECs in a scratch wound migration assay. The transplanted EPCs and COMP-Ang1 were incorporated into the blood vessels and decreased the infarct volume in the rat ischemic brain. Molecular studies revealed that COMP-Ang1 induced an interaction between Tie2 and FAK, but AKT was separated from the Tie2-FAK-AKT complex in the EPC plasma membrane. Tie2-FAK increased pp38, pSAPK/JNK, and pERK-mediated MAPK activation and interacted with integrins ανβ3, α4, β1, finally leading to migration of EPCs. AKT recruited mTOR, SDF-1, and HIF-1α to induce angiogenesis. Taken together, it is concluded that COMP-Ang1 potentiates the angiogenesis of EPCs and enhances the vascular morphogenesis indicating that combination of EPCs with COMP-Ang1 may be a potentially effective regimen for ischemic brain injury salvage therapy.

No MeSH data available.


Related in: MedlinePlus