Thoracic aortic aneurysms (TAAs) most commonly develop in the ascending region in an asymptomatic manner. Frequently, the first indication of its presence is rupture that commonly leads to death. TAAs are the life-threatening consequence in patients afflicted with a broad range of genetically determined diseases;one of the most common being Marfan's disease. The only current therapeutic strategy for individuals diagnosed with TAAs is surgical options. Consequently, there is a pressing need for mechanistic insight into TAAs to develop effective therapeutics. We have recently demonstrated that AngII infusion also leads to TAAs that are localized to the ascending aorta. AngII-induced TAAs are attenuated by CC Chemokine receptor 2 (CCR2) deficiency. This infers a role for monocyte chemoattractant protein-1 (MCP-1) in TAAs, although CCR2 also interacts with other chemokines. We have recently demonstrated that endothelial-specific deficiency of AT1a receptors imparts a similar degree of attenuation of AngII-induced TAAs as whole body CCR2 deficiency. These two observations could potentially be associated via a paracrine mechanism by which AngII stimulates MCP-1 release, the ligand that determines the major effects of CCR2 stimulation. The AngII-induced TAAs are characterized by profound medial macrophage accumulation that is predominantly on the adventitial aspect. On the basis of this briefly described background, we are proposing to test the central hypothesis that the MCP-1-CCR2 axis promotes AngII-induced TAAs localized to the ascending region through an endothelial-mediated mechanism of macrophage recruitment from the adventitia via aortic region- specific effects. To test this hypothesis, the following specific aims will be addressed:
Aim 1. Determine the role of the MCP-1-CCR2 axis in development of AngII-induced TAAs. A. Does whole body deficiency of either MCP-1 or CCR2 promote equivalent reductions in AngII-induced TAAs that are persistent and associated with reduced medial macrophage accumulation? B. Is the source of MCP-1 in promoting TAAs due to AngII releasing this chemokine directly from endothelial or indirectly via specific SMC populations? Aim 2. Determine the origin of medial macrophages accumulating in ascending aortas during development of AngII-induced TAAs. A. What is the sequence of leukocytic infiltration in the development of AngII-induced TAAs and does this correlate to the expression of MCP-1 and CCR2? B. Are macrophages that accumulate in media and adventitia of ascending aortas during AngII infusion derived from blood or tissue origin? C. Is leukocyte accumulation in human ascending aortic aneurysmal tissue associated with MCP-1 and CCR2 expression?

Public Health Relevance

Aortic aneurysmal diseases have devastating health consequences and are increasingly more common. Despite the large impact on public health, there is a relatively paucity of investigative efforts on these diseases. Consequently, there are no defined medical options developed to provide an alternative to surgical intervention. Further research in aortic aneurysmal diseases is a public health imperative.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107319-03
Application #
8644866
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Tolunay, Eser
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$529,294
Indirect Cost
$172,867
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lu, Hong; Cassis, Lisa A; Kooi, Craig W Vander et al. (2016) Structure and functions of angiotensinogen. Hypertens Res 39:492-500
Sheppard, Mary B; Daugherty, Alan; Lu, Hong (2016) Insights into ascending aortic aneurysm pathogenesis using in vivo and ex vivo imaging systems in angiotensin II-infused mice. J Thorac Dis 8:E822-4
Davis, Frank M; Rateri, Debra L; Daugherty, Alan (2015) Abdominal aortic aneurysm: novel mechanisms and therapies. Curr Opin Cardiol 30:566-73
Liu, Jing; Daugherty, Alan; Lu, Hong (2015) Angiotensin II and Abdominal Aortic Aneurysms: An update. Curr Pharm Des 21:4035-48
Mallat, Ziad; Daugherty, Alan (2015) AT1 receptor antagonism to reduce aortic expansion in Marfan syndrome: lost in translation or in need of different interpretation? Arterioscler Thromb Vasc Biol 35:e10-2
Lu, Hong; Daugherty, Alan (2015) Atherosclerosis. Arterioscler Thromb Vasc Biol 35:485-91
Poduri, Aruna; Rateri, Debra L; Howatt, Deborah A et al. (2015) Fibroblast Angiotensin II Type 1a Receptors Contribute to Angiotensin II-Induced Medial Hyperplasia in the Ascending Aorta. Arterioscler Thromb Vasc Biol 35:1995-2002
Davis, Frank M; Rateri, Debra L; Balakrishnan, Anju et al. (2015) Smooth muscle cell deletion of low-density lipoprotein receptor-related protein 1 augments angiotensin II-induced superior mesenteric arterial and ascending aortic aneurysms. Arterioscler Thromb Vasc Biol 35:155-62
Lu, Hong; Howatt, Deborah A; Balakrishnan, Anju et al. (2015) Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice. J Vis Exp :
Lu, Hong; Daugherty, Alan (2015) Regulatory B cells, interleukin-10, and atherosclerosis. Curr Opin Lipidol 26:470-1

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