TGF-β (Transforming Growth Factor-β) Signaling Protects the Thoracic and Abdominal Aorta From Angiotensin II-Induced Pathology by Distinct Mechanisms
| Autor: | Jie Hong Hu, Minghui Shi, Nathan Airhart, Stoyan N. Angelov, David A. Dichek, Hao Wei |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Pathology Aorta Thoracic Severity of Illness Index Muscle Smooth Vascular Transforming Growth Factor beta Medicine Thoracic aorta Aorta Abdominal Mice Knockout Angiotensin II Abdominal aorta Abdominal aortic aneurysm Aortic Aneurysm Phenotype Transforming Growth Factors cardiovascular system Female Tunica Media Cardiology and Cardiovascular Medicine Dilatation Pathologic Signal Transduction Adventitia medicine.medical_specialty Protein Serine-Threonine Kinases Vascular Remodeling Antibodies Article Transforming Growth Factor beta1 Transforming Growth Factor beta2 03 medical and health sciences Transforming Growth Factor beta3 medicine.artery Renin–angiotensin system Humans Animals Genetic Predisposition to Disease Aorta Aortic Aneurysm Thoracic business.industry Receptor Transforming Growth Factor-beta Type II medicine.disease Blockade Mice Inbred C57BL Disease Models Animal 030104 developmental biology business Receptors Transforming Growth Factor beta Aortic Aneurysm Abdominal Transforming growth factor |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 37:2102-2113 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvbaha.117.309401 |
| Popis: | Objective— The role of TGF-β (transforming growth factor-β) signaling in abdominal aortic aneurysm (AAA) formation is controversial. Others reported that systemic blockade of TGF-β by neutralizing antibodies accelerated AAA development in angiotensin II-infused mice. This result is consistent with other studies suggesting that TGF-β signaling prevents AAA. Development of a therapy for AAA that exploits the protective actions of TGF-β would be facilitated by identification of the mechanisms through which TGF-β prevents AAA. We hypothesized that TGF-β signaling prevents AAA by its actions on aortic medial smooth muscle cells. Approach and Results— We compared the prevalence, severity, and histopathology of angiotensin II-induced AAA among control mice (no TGF-β blockade), mice with antibody-mediated systemic neutralization of TGF-β, and mice with genetically based smooth muscle–specific loss of TGF-β signaling. Surprisingly, we found that systemic—but not smooth muscle–specific—TGF-β blockade significantly increased the prevalence of AAA and tended to increase AAA severity, adventitial thickening, and aortic wall macrophage accumulation. In contrast, abdominal aortas of mice with smooth muscle–specific loss of TGF-β signaling differed from controls only in having a thinner media. We examined thoracic aortas of the same mice. Here we found that smooth muscle–specific loss of Tgfbr2 —but not systemic TGF-β neutralization—significantly accelerated development of aortic pathology, including increased prevalence of intramural hematomas, medial thinning, and adventitial thickening. Conclusion— Our results suggest that TGF-β signaling prevents both abdominal and thoracic aneurysmal disease but does so by distinct mechanisms. Smooth muscle extrinsic signaling protects the abdominal aorta and smooth muscle intrinsic signaling protects the thoracic aorta. |
| Databáze: | OpenAIRE |
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