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. 2017 Nov;14(136):20170327.
doi: 10.1098/rsif.2017.0327.

Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension

M R Bersi  1 , R Khosravi  1 , A J Wujciak  1 , D G Harrison  2   3 , J D Humphrey  4   5
Affiliations

Differential cell-matrix mechanoadaptations and inflammation drive regional propensities to aortic fibrosis, aneurysm or dissection in hypertension

M R Bersi et al. J R Soc Interface. 2017 Nov.

Abstract

The embryonic lineage of intramural cells, microstructural organization of the extracellular matrix, local luminal and wall geometry, and haemodynamic loads vary along the length of the aorta. Yet, it remains unclear why certain diseases manifest differentially along the aorta. Toward this end, myriad animal models provide insight into diverse disease conditions-including fibrosis, aneurysm and dissection-but inherent differences across models impede general interpretations. We examined region-specific cellular, matrix, and biomechanical changes in a single experimental model of hypertension and atherosclerosis, which commonly coexist. Our findings suggest that (i) intramural cells within the ascending aorta are unable to maintain the intrinsic material stiffness of the wall, which ultimately drives aneurysmal dilatation, (ii) a mechanical stress-initiated, inflammation-driven remodelling within the descending aorta results in excessive fibrosis, and (iii) a transient loss of adventitial collagen within the suprarenal aorta contributes to dissection propensity. Smooth muscle contractility helps to control wall stress in the infrarenal aorta, which maintains mechanical properties near homeostatic levels despite elevated blood pressure. This early mechanoadaptation of the infrarenal aorta does not preclude subsequent acceleration of neointimal formation, however. Because region-specific conditions may be interdependent, as, for example, diffuse central arterial stiffening can increase cyclic haemodynamic loads on an aneurysm that is developing proximally, there is a clear need for more systematic assessments of aortic disease progression, not simply a singular focus on a particular region or condition.

Keywords: angiotensin II; aortic stiffness; inflammatory cells; smooth muscle; stress.

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Conflict of interest statement

We declare no competing interests.

Figures

Figure 1.
Figure 1.
Spatio-temporal differences in geometric, material and structural properties. Mean ± s.e.m. values of (a) distensibility MPa−1, (b) unloaded wall thickness (μm), (c) axial stretch, (d,e) circumferential and axial stress (kPa), (f,g) circumferential and axial stiffness (MPa) and (h) stored energy (kPa) from four aortic regions (ATA, DTA, SAA, IAA; see electronic supplementary material, figure S2) at six times throughout AngII infusion: baseline (0 days), 4, 7, 14, 21 and 28 days (n = 4–7 samples per group). Significant differences from baseline (0 days) denoted by +, *, **, *** p < 0.1, 0.05, 0.01, 0.001. Values for all metrics are in electronic supplementary material, table S2 and were computed at time-specific systolic pressures (electronic supplementary material, table S1), unless otherwise indicated. Note, in particular, the distinctive time course of changes in circumferential material stiffness in the ATA and circumferential stress in the SAA, with the most dramatic late thickening of the wall in the DTA and the modest changes overall in the IAA.
Figure 2.
Figure 2.
Spatio-temporal differences in wall composition and structure. (a) Representative VVG stained histological sections show wall thickness and elastin (black) from four aortic regions (ATA, DTA, SAA, IAA) at four times throughout AngII infusion: baseline (0 days), 4, 14 and 28 days. PSR staining at 28 days reveals excessive adventitial collagen deposition in three of the four regions, but especially the DTA. Quantification of layer-specific (medial—M, below dashed line and adventitial—A, above dashed line) constituent area fractions–elastin (white), collagen (medium grey), smooth muscle (SMC; light grey) and glycosaminoglycans (GAG; dark grey)—are shown for the (b) ATA, (c) DTA, (d) SAA and (e) IAA. Despite differences in elastin, collagen and SMCs, changes in GAGs were unremarkable. (f–i) Layer-specific values (mean ± s.e.m.) for cross-sectional areas from the same four regions and times are delineated for the media (dark grey) and adventitia (medium grey) (n = 10 images per group). The adventitial percentage and area increased by 28 days in all regions except the IAA. Overbar denotes statistical significance between groups, where *, **, ***p < 0.05, 0.01, 0.001. Values for all metrics are in electronic supplementary material, tables S4 and S5.
Figure 3.
Figure 3.
Spatio-temporal differences in matrix metalloproteinases and inflammatory cells. Mean ± s.e.m. values, relative to baseline, for (a) MMP-2, (b) MMP-12 and (c) MMP-13 expression, and (d) CD45+, (e) CD3+, and (f) CD68+ cell density (per mm2) from four aortic regions at four times throughout AngII infusion: baseline (0 days), 4, 14 and 28 days (n = 6 images per group). Layer-specific content is reported separately for the media (black bar) and adventitia (white bar). Overbar denotes statistical significance between groups, where *, **, ***p < 0.05, 0.01, 0.001. Values for all metrics are in electronic supplementary material, table S5.
Figure 4.
Figure 4.
Mechano-inflammatory correlates reveal a distinct time course of remodelling. Heat maps of the Pearson correlation coefficient R for pooled (a) thoracic and (b) abdominal segments (n = 8 points per correlation); blue indicates a positive and red a negative correlation. Piecewise linear fitting of the change in wall thickness versus the change in (c) CD45+ cells or (d) mean arterial pressure for all regions and times reveals an early mechano-mediated remodelling (grey region) followed by a later inflammatory-mediated remodelling (white region). Mechanoadaptation is defined by a linear relationship between normalized changes in pressure and wall thickness (i.e. formula image [21]. The time course of thickness adaptation should, therefore, mimic the nearly logarithmic behaviour of the pressure increase (cf. electronic supplementary material, figure S1). (e) Pressure- and (f) time-dependent thickness adaptation was achieved by the IAA alone (light grey circles). Data off the line of identity (black line in e), or the line of adaptation (black curve in f), indicate areas of either progressively adaptive (formula image; grey) or maladaptive (formula image; white) remodelling. Statistical significance (in a and b) is denoted by *, **, ***p < 0.05, 0.01, 0.001. All correlation coefficients and p-values are in electronic supplementary material, tables S6A–N.
Figure 5.
Figure 5.
Long-term regional differences in geometric, material and structural properties. Mean ± s.e.m. values of (a) unloaded wall thickness, (b) axial stretch, (c,d) circumferential and axial stress, (e,f) circumferential and axial stiffness, (g) distensibility and (h) stored energy from three aortic regions at four times: baseline (0d), 28 days of AngII infusion (28d), 28 days of AngII infusion followed by 196 days of no infusion (224d) and age-matched controls at 224 days without any AngII infusion (224d no AngII); n = 3 to 7 per group. Representative VVG stained sections from the (i) ATA, (j) DTA, (k) SAA and (l) IAA reveal variations in cross-sectional layer composition; mean values for each group are shown in (m–p). Note that images are representative for the 224d group only as samples with advanced disease (as in the SAA) have been excluded from all prior analyses. Scale bars represent 250 µm. Overbars denote statistical significance, where *, **, ***p < 0.05, 0.01, 0.001 and *, + and # denote differences versus 0, 28 and 224 days, respectively. Values for all metrics are in electronic supplementary material, tables S2 and S4.
Figure 6.
Figure 6.
Schematic representation of AngII mediated aortic remodelling. Early mechanical changes (pressure- and contractility-induced increases in wall stress) drive a later inflammatory response, with positive feedback (orange line) between structural stiffness and blood pressure. Common pathways can yet result in regional differences as revealed by the mechano-adaptive response in the IAA and different maladaptive (aneurysmal propensity, fibrosis, dissection propensity) responses in the other three regions. Mechano-biological and immuno-biological responses serve as central nodes that govern regional differences. Note: a red line denotes negative feedback; blue arrows represent effects on the media and green arrows represent the more pronounced effects on the adventitia. Superscript * indicates findings from references [11] and [41].
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