Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice.

Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.

Evolving structure-function relations during aortic maturation and aging revealed by multiphoton microscopy.

The evolving microstructure and mechanical properties that promote homeostasis in the aorta are fundamental to age-specific adaptations and disease progression. We combine ex vivo multiphoton microscopy and biaxial biomechanical phenotyping to quantify and correlate layer-specific microstructural parameters, for the primary extracellular matrix components (fibrillar collagen and elastic lamellae) and cells (endothelial, smooth muscle, and adventitial), with mechanical properties of the mouse aorta from weaning through natural aging up to one year. The aging endothelium was characterized by progressive reductions in cell density and altered cellular orientation. The media similarly showed a progressive decrease in smooth muscle cell density and alignment though with inter-lamellar widening from intermediate to older ages, suggesting cell hypertrophy, matrix accumulation, or both. Despite not changing in tissue thickness, the aging adventitia exhibited a marked thickening and straightening of collagen fiber bundles and reduction in cell density, suggestive of age-related remodeling not growth. Multiple microstructural changes correlated with age-related increases in circumferential and axial material stiffness, among other mechanical metrics. Because of the importance of aging as a risk factor for cardiovascular diseases, understanding the normal progression of structural and functional changes is essential when evaluating superimposed disease-related changes as a function of the age of onset.