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Computational Modeling Predicts Immuno-Mechanical Mechanisms of Maladaptive Aortic Remodeling in Hypertension
Marcos Latorre1, Matthew R Bersi2, Jay D Humphrey1,3
1Department of Biomedical Engineering Yale University, New Haven, CT, USA.
Insights
Hypertension causes aortic stiffening through inflammation-driven fibrosis. Controlling inflammation is key to preventing maladaptive changes in the aorta, but preserving matrix degradation is crucial for mechanical health.
Area of Science:
- Biomedical Engineering
- Cardiovascular Physiology
- Computational Biology
Background:
- Uncontrolled hypertension is a significant risk factor for cardiovascular diseases.
- Hypertension increases central artery stiffness, a key indicator and initiator of cardiovascular disease.
- The precise biochemomechanical mechanisms linking hypertension to aortic stiffening are not fully understood.
Purpose of the Study:
- To develop and utilize a novel computational model of aortic growth and remodeling.
- To investigate the differential effects of induced hypertension on thoracic and abdominal aortas in a mouse model.
- To elucidate constituent-level mechanisms driving aortic stiffening under hypertension.
Main Methods:
- Development of a computational model treating the aortic wall as a constrained mixture of constituents.
- Simulation of aortic growth and remodeling in response to induced hypertension in a mouse model.
- Analysis of how material properties and turnover rates of aortic wall constituents contribute to stiffening.
Main Results:
- The model successfully captured differential hypertensive effects on thoracic and abdominal aortas.
- Aorta demonstrated local mechano-adaptation to elevated blood pressure without significant inflammation.
- Marked inflammation promoted maladaptive adventitial fibrosis via increased collagen deposition without compensatory matrix degradation.
Conclusions:
- Local mechano-adaptation is possible in the aorta under hypertension.
- Inflammation drives maladaptive aortic fibrosis, primarily in the adventitia.
- Therapeutic strategies should target inflammation to reduce fibrosis while preserving matrix degradation for mechanical homeostasis.
Abstract:
Uncontrolled hypertension is a major risk factor for myriad cardiovascular diseases. Among its many effects, hypertension increases central artery stiffness which in turn is both an initiator and indicator of disease. Despite extensive clinical, animal, and basic science studies, the biochemomechanical mechanisms by which hypertension drives aortic stiffening remain unclear. In this paper, we show that a new computational model of aortic growth and remodeling can capture differential effects of induced hypertension on the thoracic and abdominal aorta in a common mouse model of disease. Because the simulations treat the aortic wall as a constrained mixture of different constituents having different material properties and rates of turnover, one can gain increased insight into underlying constituent-level mechanisms of aortic remodeling. Model results suggest that the aorta can mechano-adapt locally to blood pressure elevation in the absence of marked inflammation, but large increases in inflammation drive a persistent maladaptive phenotype characterized primarily by adventitial fibrosis. Moreover, this fibrosis appears to occur via a marked increase in the rate of deposition of collagen having different material properties in the absence of a compensatory increase in the rate of matrix degradation. Controlling inflammation thus appears to be key to reducing fibrosis, but therapeutic strategies should not compromise the proteolytic activity of the wall that is essential to mechanical homeostasis.
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