Zhaohua Cai, Min Liang, Yangjing Jiang, Haiping Chen, Yunwen Hu, Yijie Huang, Huanhuan Huo, Linghong Shen, Ben He
{"title":"Lkb1下调PVAT重塑与主动脉扩张或动脉瘤相关","authors":"Zhaohua Cai, Min Liang, Yangjing Jiang, Haiping Chen, Yunwen Hu, Yijie Huang, Huanhuan Huo, Linghong Shen, Ben He","doi":"10.1161/CIRCRESAHA.125.326297","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Perivascular adipose tissue (PVAT) is a unique adipose tissue depot that surrounds the blood vessels throughout the body. PVAT regulates vascular physiological homeostasis and contributes to the pathogenesis of vascular diseases. Lkb1 (liver kinase b1) is strongly associated with the development of cancer and cardiovascular diseases.</p><p><strong>Methods: </strong>In this study, we generated tamoxifen-inducible <i>Lkb1</i><sup><i>flox/flox</i></sup><i>;Pdgfrα-Cre</i><sup><i>ERT2</i></sup>, <i>Lkb1</i><sup><i>flox/flox</i></sup>;<i>Pdgfrβ-Cre</i><sup><i>ERT2</i></sup>, and <i>Lkb1</i><sup><i>flox/flox</i></sup>;<i>Myh11-Cre</i><sup><i>ERT2</i></sup> mice to investigate the role of Lkb1 in PVAT and related vessel function.</p><p><strong>Results: </strong>We found that Lkb1 is a PVAT-enriched gene that is strikingly downregulated during Ang II (angiotensin II)-induced aortic aneurysm formation. Lkb1 deficiency in Pdgfrα<sup>+</sup> fibroblast induces PVAT dysfunction, which in turn results in gradual aortic dilation and exaggerates Ang II-induced aortic aneurysm formation in mice. In addition, Lkb1 deficiency in Myh11<sup>+</sup> (smooth muscle myosin heavy chain 11) or Pdgfrβ<sup>+</sup> (platelet-derived growth factor receptor beta) mural cells leads to PVAT dysfunction and spontaneous aortic dilation or aneurysm formation. Mechanistically, genetic deletion of Lkb1 activates renin-angiotensin system in PVAT, which drives vascular smooth muscle cell phenotype switching via paracrine signaling. Most importantly, treatment with either renin inhibitor aliskiren or Ang II receptor blocker valsartan rescues vascular smooth muscle cell phenotypic switching and aortic dilation in <i>Lkb1</i><sup><i>flox/flox</i></sup>;<i>Pdgfrα-Cre</i><sup><i>ERT2</i></sup> mice.</p><p><strong>Conclusions: </strong>Our work strongly suggests that Lkb1 deficiency in PVAT drives vascular smooth muscle cell phenotypic switching and aortic dilation and aneurysm formation. Lkb1, via its regulation of renin-angiotensin system in PVAT, maintains vessel homeostasis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1006-1023"},"PeriodicalIF":16.2000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lkb1 Downregulation Links PVAT Remodeling to Aortic Dilation or Aneurysm.\",\"authors\":\"Zhaohua Cai, Min Liang, Yangjing Jiang, Haiping Chen, Yunwen Hu, Yijie Huang, Huanhuan Huo, Linghong Shen, Ben He\",\"doi\":\"10.1161/CIRCRESAHA.125.326297\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Perivascular adipose tissue (PVAT) is a unique adipose tissue depot that surrounds the blood vessels throughout the body. PVAT regulates vascular physiological homeostasis and contributes to the pathogenesis of vascular diseases. Lkb1 (liver kinase b1) is strongly associated with the development of cancer and cardiovascular diseases.</p><p><strong>Methods: </strong>In this study, we generated tamoxifen-inducible <i>Lkb1</i><sup><i>flox/flox</i></sup><i>;Pdgfrα-Cre</i><sup><i>ERT2</i></sup>, <i>Lkb1</i><sup><i>flox/flox</i></sup>;<i>Pdgfrβ-Cre</i><sup><i>ERT2</i></sup>, and <i>Lkb1</i><sup><i>flox/flox</i></sup>;<i>Myh11-Cre</i><sup><i>ERT2</i></sup> mice to investigate the role of Lkb1 in PVAT and related vessel function.</p><p><strong>Results: </strong>We found that Lkb1 is a PVAT-enriched gene that is strikingly downregulated during Ang II (angiotensin II)-induced aortic aneurysm formation. Lkb1 deficiency in Pdgfrα<sup>+</sup> fibroblast induces PVAT dysfunction, which in turn results in gradual aortic dilation and exaggerates Ang II-induced aortic aneurysm formation in mice. In addition, Lkb1 deficiency in Myh11<sup>+</sup> (smooth muscle myosin heavy chain 11) or Pdgfrβ<sup>+</sup> (platelet-derived growth factor receptor beta) mural cells leads to PVAT dysfunction and spontaneous aortic dilation or aneurysm formation. Mechanistically, genetic deletion of Lkb1 activates renin-angiotensin system in PVAT, which drives vascular smooth muscle cell phenotype switching via paracrine signaling. Most importantly, treatment with either renin inhibitor aliskiren or Ang II receptor blocker valsartan rescues vascular smooth muscle cell phenotypic switching and aortic dilation in <i>Lkb1</i><sup><i>flox/flox</i></sup>;<i>Pdgfrα-Cre</i><sup><i>ERT2</i></sup> mice.</p><p><strong>Conclusions: </strong>Our work strongly suggests that Lkb1 deficiency in PVAT drives vascular smooth muscle cell phenotypic switching and aortic dilation and aneurysm formation. Lkb1, via its regulation of renin-angiotensin system in PVAT, maintains vessel homeostasis.</p>\",\"PeriodicalId\":10147,\"journal\":{\"name\":\"Circulation research\",\"volume\":\" \",\"pages\":\"1006-1023\"},\"PeriodicalIF\":16.2000,\"publicationDate\":\"2025-09-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCRESAHA.125.326297\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCRESAHA.125.326297","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/26 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
Lkb1 Downregulation Links PVAT Remodeling to Aortic Dilation or Aneurysm.
Background: Perivascular adipose tissue (PVAT) is a unique adipose tissue depot that surrounds the blood vessels throughout the body. PVAT regulates vascular physiological homeostasis and contributes to the pathogenesis of vascular diseases. Lkb1 (liver kinase b1) is strongly associated with the development of cancer and cardiovascular diseases.
Methods: In this study, we generated tamoxifen-inducible Lkb1flox/flox;Pdgfrα-CreERT2, Lkb1flox/flox;Pdgfrβ-CreERT2, and Lkb1flox/flox;Myh11-CreERT2 mice to investigate the role of Lkb1 in PVAT and related vessel function.
Results: We found that Lkb1 is a PVAT-enriched gene that is strikingly downregulated during Ang II (angiotensin II)-induced aortic aneurysm formation. Lkb1 deficiency in Pdgfrα+ fibroblast induces PVAT dysfunction, which in turn results in gradual aortic dilation and exaggerates Ang II-induced aortic aneurysm formation in mice. In addition, Lkb1 deficiency in Myh11+ (smooth muscle myosin heavy chain 11) or Pdgfrβ+ (platelet-derived growth factor receptor beta) mural cells leads to PVAT dysfunction and spontaneous aortic dilation or aneurysm formation. Mechanistically, genetic deletion of Lkb1 activates renin-angiotensin system in PVAT, which drives vascular smooth muscle cell phenotype switching via paracrine signaling. Most importantly, treatment with either renin inhibitor aliskiren or Ang II receptor blocker valsartan rescues vascular smooth muscle cell phenotypic switching and aortic dilation in Lkb1flox/flox;Pdgfrα-CreERT2 mice.
Conclusions: Our work strongly suggests that Lkb1 deficiency in PVAT drives vascular smooth muscle cell phenotypic switching and aortic dilation and aneurysm formation. Lkb1, via its regulation of renin-angiotensin system in PVAT, maintains vessel homeostasis.
期刊介绍：
Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies.
Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities.
In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field.
Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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