Vascular stiffening in aging females with a hypertension‐induced HIF2A gain‐of‐function mutation

Figures

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  FIGURE 1. Sex differences in survival rates in WT and Hif2a mice with aging. Kaplan–Meier survival analysis for WT, Hif2a HT, and Hif2a HO (a) female (N = 65) and (b) male mice (N = 64). Significance level is set at *p < 0.05 for a log‐rank (Mantel‐Cox) test.

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  FIGURE 2. Female Hif2a HT mice exhibit compromised vascular mechanics because of aging‐dependent disease progression. (a) Exponential fits of tensile curves of circumferential tensile testing (CTT) of young adult (YA, 8–16 weeks) and middle age (M, 9–12 months) female WT thoracic aorta segments (i), ultimate tensile stress (ii), and strain at failure (iii) (N = 6–11, n = 2–4). (b) Exponential fits of tensile curves of CTT of young adult (YA, 8–16 weeks) and middle age (M, 9–12 months) female Hif2a HT thoracic aorta segments (i), ultimate tensile stress (ii), and strain at failure (iii) (N = 5–10, n = 2–4). (c) Exponential fits of tensile curves of CTT of young adult (YA, 8–16 weeks) and middle age (M, 9–12 months) male WT thoracic aorta segments (i), ultimate tensile stress (ii), and strain at failure (iii). (N = 6–7, n = 2–4). (d) Exponential fits of tensile curves of circumferential tensile testing (CTT) of young adult (YA, 8–16 weeks) and middle age (M, 9–12 months) male Hif2a HT thoracic aorta segments (i), ultimate tensile stress (ii), and strain at failure (iii) (N = 7, n = 2–4). Solid lines indicate cellular segments, dashed lines indicate acellular segments, and dotted lines…

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  FIGURE 3. Hif2a HT middle age female mice exhibit a thicker adventitial layer than their wildtype counterparts. (a) Representative 40× histological images of Masson's Trichrome (MAS) and Verhoeff‐Van Gieson (VVG) stained of young adult (YA, 8–16 weeks) and middle age (M, 9–12 months) female WT and Hif2a HT mouse thoracic aorta. Scale bar is 75 μm. (b) Quantification of histological images of adventitial layer thickness (i), medial layer thickness (ii), and adventitial/media thickness ratio (iii) (N = 3–7). Significance level is set at *p < 0.05 for a two‐way ANOVA (multiple comparisons performed using Tukey's test).

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  FIGURE 4. Middle age female Hif2a HT mice exhibit increased collagens I and III compared to wild‐type counterparts. (a) qRT‐PCR of relative expression of ELN, COL1A1, and COL3a1 transcripts in young adult (YA, 8–16 weeks) and middle age (M, 8–12 months) female WT and Hif2a HT mice (N = 3–4, n = 2). (b) Representative 40× IHC images of collagen I and collagen III in young adult (YA, 8–16 weeks) and middle age (M, 8–12 months) female WT and Hif2a HT mice (N = 3–7, n = 10–40). Bottom row are high‐magnification of the boxed areas for collagen III (green squares) (i) top scale bar is 50 μm, bottom scale bar is 10 μm. Yellow arrows mark collagen + regions of the medial layer. (c) Percentage of vessel area positive for collagens I and III + area (ii) (N = 3–7, n = 20–40). Significance level is set at *p < 0.05 for a t‐test (Kolmogorov–Smirnov comparison).