Maladaptive aortic remodeling in hypertension associates with dysfunctional smooth muscle contractility

Intramural cells are responsible for establishing, maintaining, and restoring the functional capability and structural integrity of the aortic wall. In response to hypertensive loading, these cells tend to increase wall content via extracellular matrix turnover in an attempt to return wall stress and/or material stiffness toward homeostatic values despite the elevated pressure. Using a common rodent model of induced hypertension, we found marked mouse-to-mouse differences in thoracic aortic remodeling over 2-4 wk of pressure elevation, with mechanoadaptation in some but gross maladaptation in most mice despite the same experimental conditions and overall genetic background. Consistent with our hypothesis, we also found a strong correlation between maladaptive aortic remodeling and a dysfunctional ability of the vessel to vasoconstrict, with maladaptation often evidenced by marked adventitial fibrosis. Remarkably, mouse-to-mouse variability did not correlate with the degree or duration of pressure elevation over the 2- to 4-wk study period. These findings suggest both a need to study together the structure, mechanical properties, and function across layers of the wall when assessing aortic health and a need for caution in using common statistical comparisons across small seemingly well-defined groups that may mask important underlying individual responses, an area of investigation that demands increasing attention as we move toward an era of precision diagnosis and patient care. NEW & NOTEWORTHY There are three primary findings. Marked mouse-to-mouse differences exist in large vessel hypertensive remodeling in an otherwise equivalent cohort of animals. The degree of maladaptation correlates strongly with decreases in smooth muscle contractile capacity. Finally, short-term maladaptive remodeling is independent of the precise degree or duration of the pressure elevation provided that thresholds are exceeded. Therapeutic targets should thus be personalized and focus on both layer-to-layer interactions and early interventions.