Abstract P2066: Age-related Changes In Posttranscriptional Regulation Of Macrophage VEGF As A Mechanism Of Impaired Inflammatory Arteriogenesis
| Autor: | Chris S Mantsounga, Sheila Sharma, Cadence Lee, Jade Neverson, Rachel Carley, Gaurav Choudhary, Alan R Morrison |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Circulation Research. 131 |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/res.131.suppl_1.p2066 |
| Popis: | Aging and age-related diseases like peripheral arterial disease are associated with impaired inflammatoryarteriogenesis in response to injury. During ischemia, macrophage recruitment and macrophage pro-angiogenic VEGF-A isoform expression contribute to post developmental arteriogenesis. Preliminary datafrom bone marrow-derived macrophages (BMDMs) demonstrated decreased VEGF-A level by both mRNAand protein in aged (52-week-old) and advanced aged (104-week-old) mice when compared to young (12-week-old). Moreover, VEGF-A165a which is VEGF-A proangiogenic splice variant was also reduced inmacrophages from aged and advanced aged mice. The anti-angiogenic VEGF-A165b variant wassignificantly increased in advanced aged mice. We sought to determine the mechanisms which cancontribute to the reduction of pro-angiogenic VEGF-A and consequently reduced inflammatory-mediatedarteriogenesis response in the context of aging. In a hindlimb ischemia model of angio/arteriogenesis, wefound decreased blood flow recovery in aged mice. Moreover, small arterial angiography by microCTconfirmed decreased arteriogenesis. Loss of functional arteriogenesis was associated with decreased muscletissue VEGF-A and VEGF-A165a levels despite adequate macrophage recruitment to the muscle tissue.Moreover, VEGF-A165b was increased in ischemic tissue from advanced aged mice. The mechanism ofreduced macrophage pro-angiogenic VEGF-A165a expression involved decreased mRNA stability withdecreased association of VEGF-A165a mRNA with the RNA-stabilizing protein HuR. In fact, aged BMDMsdemonstrated a loss of HuR binding to VEGF-A165a mRNA with decreased VEGF-A165a mRNA half-life,and consequently decreased inflammatory angio/arteriogenesis. |
| Databáze: | OpenAIRE |
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