Excessive Adventitial Remodeling Leads to Early Aortic Maladaptation in Angiotensin-Induced Hypertension

Abstract

The primary function of central arteries is to store elastic energy during systole and to use it to sustain blood flow during diastole. Arterial stiffening compromises this normal mechanical function and adversely affects end organs, such as the brain, heart, and kidneys. Using an angiotensin II infusion model of hypertension in wild-type mice, we show that the thoracic aorta exhibits a dramatic loss of energy storage within 2 weeks that persists for at least 4 weeks. This diminished mechanical functionality results from increased structural stiffening as a result of an excessive accumulation of adventitial collagen, not a change in the intrinsic stiffness of the wall. A detailed analysis of the transmural biaxial wall stress suggests that the exuberant production of collagen results more from an inflammatory response than from a mechano-adaptation, hence reinforcing the need to control inflammation, not just blood pressure. Although most clinical assessments of arterial stiffening focus on intimal-medial thickening, these results suggest a need to measure and control the highly active and important adventitia.

Keywords: arterial stiffness; collagen; elastic energy; hypertension; wall stress.

Figure 1

Mechanical testing of the proximal descending thoracic aorta from Sham (n=5, black), 2-week (n=5, grey) and 4-week (n=5, white circles) angiotensin-infused mice (mean ± SEM). (A) Pressure-diameter curves at group-specific in vivo axial stretches and (B) axial force-length curves at 100 mmHg plus associated mean (C) circumferential and (D) axial stress-stretch curves. Iso-energy contours for (E) Sham and (F) angiotensin-infused mice (2-week, black; 4-week, grey) wherein filled circles represent the elastically stored energy at group-specific systolic pressures and in vivo axial stretches and solid lines represent the energy level at any biaxial state.

Figure 2

Comparison of morphometric, material, and structural metrics for aortas from Sham (black), 2-week (grey) and 4-week (white) angiotensin-infused mice at group-specific systolic pressures. (A) In vivo axial stretch, (B) wall thickness, mean (C) circumferential and (D) axial wall stress, overall (E) circumferential and (F) axial material stiffness, (G) distensibility, and (H) energy storage. See Online Data Supplement for descriptions of these mechanical quantities (Table S1). ***P < 0.001 between groups.

Figure 3

Histological analysis and layer-specific wall composition for representative Sham (A, top row) and 2-week angiotensin-infused (A, bottom row) mice. (A) Stained sections show distributions of elastin (black in VVG), smooth muscle (red in MTC), and collagen (blue in MTC and green-red in PSR). (B) Quantitative area fraction analysis for elastin (white), smooth muscle (light-grey), and collagen (dark-grey) in the media (below dashed line) and adventitia (above dashed line).

Figure 4

Transmural distributions of biaxial stress and material stiffness for Sham (black) and 2-week angiotensin-infused (grey) mice. Predicted layer-specific distributions of circumferential and axial (A,B) stress and (C,D) material stiffness at group-specific in vivo axial stretches and mean arterial pressures within the medial (M) and adventitial (A) layers. Mean circumferential stress computed via the Laplace equation (in A, dashed line; Eq. S.4.1) and the integral means of material stiffness (in C, D, dashed lines) are shown for comparison. (E) Circumferential and (F) axial stress distributions are shown for a simulated step-increase from Sham to Ang II systolic pressure; annotations show layer-specific percent changes in biaxial stress. Normalized radius ranges from 0 (inner wall) to 1 (outer wall), and vertical solid lines (light-grey) denote the predicted medial-adventitial border (0.68 for Sham and 0.43 for Ang II, similar to that in Figure 3B).