Stiffening of central arteries (i.e., the aorta and carotids) is now recognized as a strong indicator and initiator of cardiovascular, neurovascular, and renovascular diseases. Active searches are underway both to identify the best clinical metric of increased arterial stiffness and to find de-stiffening drugs that can lower disease ris. Amongst the metrics considered, carotid-femoral pulse wave velocity (cf-PWV) has emerged as the gold standard for assessing stiffness and the potential efficacy of de-stiffening drugs. Yet, given that arteries stiffen differentially by region and that cf-PWV yields information that is necessarily averaged over a large portion of the central vasculature, we submit that there is a need to assess better its potential as an early indicator of arterial stiffening. That is, it may b that by the time cf-PWV increases to a diagnostic value, underlying structural and mechanical changes may be largely entrenched and thereby less amenable to treatment. The goals of this project are to build on a very successful first 4-year funding period (25 papers + 10 expected soon) and to quantify and compare, for the first time, the progression of regional differences in large artery stiffening in four diverse mouse models that collectively address four key aspects of human hyper- tension, namely, endothelial dysfunction, effects of salt loading, and excess systemic vs. local angiotensin-II. These models also depend, in part, on inflammation, which is increasingly recognized as an important contributor to hypertension and vascular aging. Progressive, regional, stiffening of 5 arteries (carotid, descending thoracic, suprarenal abdominal, infrarenal abdominal, and iliac) will be quantified via in vivo data as well as novel computer-controlled in vitro biaxial tests. These data, in turn, will be used to extend and inform novel fluid-solid-interaction computational model that will be validated with available data and then used to assess the effects of evolving regional differences in wall properties on cf-PWV and, importantly, the pulse pressures at the levels of the heart and kidney. It is, of course, the increased pulse pressures in the coronary and renal vasculature that is the true concern of hypertension. Finally, we will also assess the potential efficacy of two drugs, an angiotensin-II type 1 receptor antagonist and an anti-inflammatory agent, again using the most comprehensive structural, mechanical, and hemodynamic assessments to date. This project is highly significant for it will reveal unprecedented insight into fundamental structural and mechanical mechanisms that underlie central arterial stiffening and its effects on central hemodynamics, which is increasingly important to large segments of our society - hypertensive, the elderly, diabetics, the obese, transplant recipients, and even those treated for AIDS. This project is innovative for i will couple novel experimental methods and computational models to study together four different mouse models that represent a broad spectrum of contributors to human hypertension as well as the efficacy of two potential treatments of both.

Public Health Relevance

Central artery stiffening is a well-established initiator and indicator of cardiovascular disease; it arises in hyper- tension, aging, diabetes, obesity, connective tissue disorders such as Marfan syndrome, organ transplantation, and the treatment of AIDS patients. Such stiffening contributes to heart disease and end-stage kidney failure. This project will use four diverse mouse models of hypertension and computer models to identify improved methods of diagnosing and treating central arterial stiffening, which promises to improve health care for many.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL105297-05A1
Application #
9106821
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
OH, Youngsuk
Project Start
2010-09-30
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Ferruzzi, Jacopo; Di Achille, Paolo; Tellides, George et al. (2018) Combining in vivo and in vitro biomechanical data reveals key roles of perivascular tethering in central artery function. PLoS One 13:e0201379
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Korneva, A; Zilberberg, L; Rifkin, D B et al. (2018) Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome. Biomech Model Mechanobiol :
Cuomo, Federica; Roccabianca, Sara; Dillon-Murphy, Desmond et al. (2017) Effects of age-associated regional changes in aortic stiffness on human hemodynamics revealed by computational modeling. PLoS One 12:e0173177
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Bellini, C; Bersi, M R; Caulk, A W et al. (2017) Comparison of 10 murine models reveals a distinct biomechanical phenotype in thoracic aortic aneurysms. J R Soc Interface 14:
Oh, Young S; Berkowitz, Dan E; Cohen, Richard A et al. (2017) A Special Report on the NHLBI Initiative to Study Cellular and Molecular Mechanisms of Arterial Stiffness and Its Association With Hypertension. Circ Res 121:1216-1218

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