Aortic aneurysms are common pathologies often associated with tear (dissection) and rupture of the vessel wall. Despite substantial research effort, therapeutic options to prevent death from ruptured aortic aneurysm remain limited. In contrast to abdominal aortic aneurysm (AAA), thoracic aortic aneurysm (TAA) is frequently caused by mutations in proteins that promote arterial tissue integrity and homeostasis. Characterization of pathogenic mechanism of aortic aneurysms in genetically altered or experimentally manipulated mice has identified both common and unique disease determinants, in addition to raising some controversies. Unresolved issues relevant to the development of new therapeutic strategies include the mechanisms of improper signaling by angiotensin II type I receptor (AT1r) and by TGF? in the dilating aorta. We propose to use a monogenic mouse model of TAA to address these key issues with the long-term goal of identifying new biological targets for drug therapy. The premise of our studies rests on strong preliminary evidence indicating that wall stress is a primary activator of persistent AT1r signaling and that the homeodomaininteracting protein kinase 2 (Hipk2) is an unsuspected stimulator of TGF? hyperactivity activated by AT1rinduced reactive oxygen species (ROS) signaling. We therefore hypothesize that progressive hemodynamic load on a biomechanically impaired aorta triggers stress signals that are sensed and mediated by AT1r via ROS to augment TGF? activity in part through Hipk2 action. We will test our hypothesis by monitoring TAA modifications in MFS mice with different genetic and pharmacological manipulations of the AT1 and AT2 receptors (Aim 1a and Aim 1b); by analyzing the molecular responses of healthy and mutant aortic strips to ex vivo stretching (Aim 1c); by elucidating the pathogenic contribution of Hipk2 to TAA formation in relationship to improper AT1r and TGF? signaling (Aim 2a); by supporting the in vivo findings with molecular and biochemical analyses of Hipk2 dysregulation in mutant vascular smooth muscle cell cultures (Aim 2b); and by validating mouse derived evidence of Hipk2related molecular abnormalities in aortic tissue specimens isolated from MFS patients (Aim 2c). The proposed work is expected to shed new light on the structural, molecular and mechanical determinants of aortic aneurysms and identify potential drug targets to blunt arterial disease. As such, our work is predicted to advance basic scientific knowledge, improve clinical care and guide translational applications for this life-threatening group of arterial disease conditions.

Public Health Relevance

Permanent dilation of the aorta (aneurysm) is a common and often lethal vascular disease that remains an unmet medical challenge, in spite of much research effort. This application seeks to advance fundamental knowledge of the molecular mechanisms driving aortic aneurysms in a well-defined genetic model of the human disease with the long-term goal of developing more effective, evidence based therapies for afflicted patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126173-04
Application #
9525391
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Tolunay, Eser
Project Start
2015-07-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Ramirez, Francesco; Caescu, Cristina; Wondimu, Elisabeth et al. (2018) Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGF? signaling and cell stemness. Matrix Biol 71-72:82-89
Galatioto, Josephine; Caescu, Cristina I; Hansen, Jens et al. (2018) Cell Type-Specific Contributions of the Angiotensin II Type 1a Receptor to Aorta Homeostasis and Aneurysmal Disease-Brief Report. Arterioscler Thromb Vasc Biol 38:588-591
Milewicz, Dianna M; Prakash, Siddharth K; Ramirez, Francesco (2017) Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models. Annu Rev Med 68:51-67
Bellini, C; Korneva, A; Zilberberg, L et al. (2016) Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome. J Biomech 49:2383-2389
Lee, Jia-Jye; Galatioto, Josephine; Rao, Satish et al. (2016) Losartan Attenuates Degradation of Aorta and Lung Tissue Micromechanics in a Mouse Model of Severe Marfan Syndrome. Ann Biomed Eng 44:2994-3006
Ferruzzi, J; Bersi, M R; Mecham, R P et al. (2016) Loss of Elastic Fiber Integrity Compromises Common Carotid Artery Function: Implications for Vascular Aging. Artery Res 14:41-52