Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice
Background. Aging is a major risk factor for cardiovascular disease. Cysteine protease cathepsin K (CatK) has been implicated in the process of angiogenesis, but the exact roles of individual CatK in vessel formation during aging are poorly understood. Methods and Results. To study the putative role...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-01-01
|
| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2020/6938620 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832566136525291520 |
|---|---|
| author | Xueling Yue Haiying Jiang Ying Xu Manli Xia Xian-Wu Cheng |
| author_facet | Xueling Yue Haiying Jiang Ying Xu Manli Xia Xian-Wu Cheng |
| author_sort | Xueling Yue |
| collection | DOAJ |
| description | Background. Aging is a major risk factor for cardiovascular disease. Cysteine protease cathepsin K (CatK) has been implicated in the process of angiogenesis, but the exact roles of individual CatK in vessel formation during aging are poorly understood. Methods and Results. To study the putative role of CatK in ischemia-induced angiogenesis, we applied a hindlimb ischemia model to aged wild-type (CatK+/+) and CatK-deficient (CatK−/−) mice. A serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in the aged CatK−/−mice was impaired throughout the follow-up period. On postoperative day 14, CatK deficiency had also impaired capillary formation. CatK deficiency reduced the levels of cleaved Notch1, phospho-Akt, and/or vascular endothelial growth factor (VEGF) proteins in the ischemic muscles and bone marrow-derived c-Kit+ cells. A flow cytometry analysis revealed that CatK deficiency reduced the numbers of endothelial progenitor cell (EPC)-like CD31+/c-Kit+ cells in the peripheral blood as well as the ischemic vasculature. In vitro experiments, CatK−/− impaired bone-derived c-Kit+ cellular functions (migration, invasion, proliferation, and tubulogenesis) in aged mice. Our findings demonstrated that aging impaired the ischemia-induced angiogenesis associated with the reductions of the production and mobilization of CD31+/c-Kit+ cells in mice. Conclusions. These findings established that the impairment of ischemia-induced neovascularization in aged CatK−/− mice is due, at least in part, to the reduction of EPC mobilization and the homing of the cells into vasculature that is associated with the impairment of Notch1 signaling activation at advanced ages. |
| format | Article |
| id | doaj-art-6941fb2c8aef4ed89f9ad8622c69f809 |
| institution | Kabale University |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Stem Cells International |
| spelling | doaj-art-6941fb2c8aef4ed89f9ad8622c69f8092025-02-03T01:05:03ZengWileyStem Cells International1687-966X1687-96782020-01-01202010.1155/2020/69386206938620Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged MiceXueling Yue0Haiying Jiang1Ying Xu2Manli Xia3Xian-Wu Cheng4Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji, Jilin 133000, ChinaDepartment of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing 314001, ChinaDepartment of Cardiology and Hypertension, Yanbian University Hospital, Yanji, Jilin 133000, ChinaDepartment of Cardiology and Hypertension, Yanbian University Hospital, Yanji, Jilin 133000, ChinaDepartment of Cardiology and Hypertension, Yanbian University Hospital, Yanji, Jilin 133000, ChinaBackground. Aging is a major risk factor for cardiovascular disease. Cysteine protease cathepsin K (CatK) has been implicated in the process of angiogenesis, but the exact roles of individual CatK in vessel formation during aging are poorly understood. Methods and Results. To study the putative role of CatK in ischemia-induced angiogenesis, we applied a hindlimb ischemia model to aged wild-type (CatK+/+) and CatK-deficient (CatK−/−) mice. A serial laser Doppler blood-flow analysis revealed that the recovery of the ischemic/normal blood-flow ratio in the aged CatK−/−mice was impaired throughout the follow-up period. On postoperative day 14, CatK deficiency had also impaired capillary formation. CatK deficiency reduced the levels of cleaved Notch1, phospho-Akt, and/or vascular endothelial growth factor (VEGF) proteins in the ischemic muscles and bone marrow-derived c-Kit+ cells. A flow cytometry analysis revealed that CatK deficiency reduced the numbers of endothelial progenitor cell (EPC)-like CD31+/c-Kit+ cells in the peripheral blood as well as the ischemic vasculature. In vitro experiments, CatK−/− impaired bone-derived c-Kit+ cellular functions (migration, invasion, proliferation, and tubulogenesis) in aged mice. Our findings demonstrated that aging impaired the ischemia-induced angiogenesis associated with the reductions of the production and mobilization of CD31+/c-Kit+ cells in mice. Conclusions. These findings established that the impairment of ischemia-induced neovascularization in aged CatK−/− mice is due, at least in part, to the reduction of EPC mobilization and the homing of the cells into vasculature that is associated with the impairment of Notch1 signaling activation at advanced ages.http://dx.doi.org/10.1155/2020/6938620 |
| spellingShingle | Xueling Yue Haiying Jiang Ying Xu Manli Xia Xian-Wu Cheng Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice Stem Cells International |
| title | Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice |
| title_full | Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice |
| title_fullStr | Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice |
| title_full_unstemmed | Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice |
| title_short | Cathepsin K Deficiency Impaired Ischemia-Induced Neovascularization in Aged Mice |
| title_sort | cathepsin k deficiency impaired ischemia induced neovascularization in aged mice |
| url | http://dx.doi.org/10.1155/2020/6938620 |
| work_keys_str_mv | AT xuelingyue cathepsinkdeficiencyimpairedischemiainducedneovascularizationinagedmice AT haiyingjiang cathepsinkdeficiencyimpairedischemiainducedneovascularizationinagedmice AT yingxu cathepsinkdeficiencyimpairedischemiainducedneovascularizationinagedmice AT manlixia cathepsinkdeficiencyimpairedischemiainducedneovascularizationinagedmice AT xianwucheng cathepsinkdeficiencyimpairedischemiainducedneovascularizationinagedmice |