Research ArticleMARFAN SYNDROME

Oxytocin antagonism prevents pregnancy-associated aortic dissection in a mouse model of Marfan syndrome

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Science Translational Medicine  01 May 2019:
Vol. 11, Issue 490, eaat4822
DOI: 10.1126/scitranslmed.aat4822
  • Fig. 1 The effects of pregnancy in WT and Fbn1mgR/mgRmice.

    (A) Kaplan-Meier survival curve for lactating Fbn1mgR/mgR mice (n = 45) compared to male (n = 63) or never-pregnant female (n = 60) Fbn1mgR/mgR mice. (B) Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy (3 weeks) and lactation (4 weeks) in WT never-pregnant (n = 33), WT lactating (n = 30), Fbn1mgR/mgR never-pregnant (n = 60), and Fbn1mgR/mgR lactating (n = 35) mice, as measured by echocardiogram. Survival was statistically evaluated using a log-rank (Mantel-Cox) test. When data are presented as boxplots, the box extends from the 25th to 75th percentiles, median is denoted by the internal line, and whiskers indicate the range calculated using the Tukey method, with data points outside the whiskers shown as individual points. All significant P values (P < 0.05) are noted in the figure.

  • Fig. 2 Therapeutic manipulations that alter the survival and aortic growth in pregnancy.

    (A) Kaplan-Meier survival curve comparing Fbn1mgR/mgR never-pregnant (n = 60) and Fbn1mgR/mgR lactating (n = 45) mice to Fbn1mgR/mgR females with pups removed on the day of delivery, thereby preventing lactation and eliminating the lactation-induced prolonged elevation of oxytocin (n = 27). (B) Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy (3 weeks) and lactation (4 weeks) in Fbn1mgR/mgR never-pregnant (n = 60), Fbn1mgR/mgR lactating (n = 35), and Fbn1mgR/mgR females with pups removed (n = 20). (C) Representative proximal ascending aortic wall sections stained with VVG for elastin, demonstrating elastic fiber breaks (white arrows), cellularity, and thickness of the adventitia (black asterisks) in the Fbn1mgR/mgR and WT mice. (D) Kaplan-Meier survival curve comparing Fbn1mgR/mgR lactating mice (n = 45) to Fbn1mgR/mgR females with OTA administered via a continuous subcutaneous infusion pump implanted at the beginning of the third week of gestation and continued through the 4 weeks of lactation for a total of 5 weeks of treatment (n = 19). (E) Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy and lactation in never-pregnant (n = 60), lactating (n = 35), and OTA-treated (n = 15) Fbn1mgR/mgR mice. (F) Kaplan-Meier survival curve assessing the effect of OA administration to never-pregnant Fbn1mgR/mgR mice (n = 10) via a continuous subcutaneous infusion pump implanted at 7 weeks of life and continued for a total of 5 weeks of treatment to mimic the time span of the third week of gestation and 4 weeks of lactation. (G) Kaplan-Meier survival curve assessing the effects of OA administered to Fbn1mgR/mgR mice (n = 10) via a continuous subcutaneous infusion pump implanted at the beginning of the third week of gestation and continued through the 4 weeks of lactation for a total of 5 weeks of treatment. Survival was statistically evaluated using a log-rank (Mantel-Cox) test. When data are presented as boxplots, the box extends from the 25th to 75th percentiles, median is denoted by the internal line, and whiskers indicate the range calculated using the Tukey method, with data points outside the whiskers shown as individual points. All significant P values (P < 0.05) are noted in the figure.

  • Fig. 3 Therapeutic effect of antihypertensive therapy in pregnancy.

    (A) Kaplan-Meier survival curve comparing the effects of propranolol treatment (n = 7) versus hydralazine treatment (n = 20) in Fbn1mgR/mgR mice. Treatment with propranolol or hydralazine was initiated at the beginning of the third week of pregnancy and continued through the 4 weeks of lactation. (B) Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy and lactation, as measured by echocardiogram, in never-pregnant (n = 60) versus lactating Fbn1mgR/mgR mice treated with placebo (n = 35), hydralazine (n = 28), or propranolol (n = 7). (C) Average systolic and diastolic blood pressure in never-pregnant and in lactating placebo-, hydralazine-, and propranolol-treated Fbn1mgR/mgR mice (n = 4 for each treatment group). Survival was statistically evaluated using a log-rank (Mantel-Cox) test. When data are presented as boxplots, the box extends from the 25th to 75th percentiles, median is denoted by the internal line, and whiskers indicate the range calculated using the Tukey method, with data points outside the whiskers shown as individual points. All significant P values (P < 0.05) are noted in the figure.

  • Fig. 4 ERK1/2 phosphorylation in the aorta and its correlation with aortic dissection and aneurysm.

    (A) Western blot analysis of pERK1/2 in the aortic root and proximal ascending aorta in WT never-pregnant, WT lactating, Fbn1mgR/mgR never-pregnant, and Fbn1mgR/mgR lactating mice (n = 4 for each treatment group). (B) Western blot analysis of pERK1/2 in the aortic root and proximal ascending aorta comparing WT never-pregnant (n = 3) and lactating mice (n = 3), Fbn1mgR/mgR never-pregnant (n = 4) and lactating (n = 4) mice, Fbn1mgR/mgR mice with pups removed thereby preventing lactation (n = 3), and Fbn1mgR/mgR mice treated with OTA (n = 3) or hydralazine (n = 3). (C) pERK IF of the aortic root and ascending aorta in representative WT and Fbn1mgR/mgR never-pregnant, lactating, and lactating Fbn1mgR/mgR treated with OTA. Scale bars, 50 μm. DAPI, 4′,6-diamidino-2-phenylindole. (D) Kaplan-Meier curve demonstrating the survival of Fbn1mgR/mgR lactating mice treated with trametinib (n = 20), initiated at the start of the third week of pregnancy and continued through 4 weeks of lactation, in comparison to untreated Fbn1mgR/mgR mice (n = 45). (E) Average aortic root and proximal ascending aortic growth over the 7 weeks spanning pregnancy and lactation in Fbn1mgR/mgR never-pregnant (n = 60) or lactating Fbn1mgR/mgR mice treated with placebo (n = 35) or trametinib (n = 25). (F) Western blot analysis of pERK1/2 in the aortic root and proximal ascending aorta comparing lactating Fbn1mgR/mgR mice treated with placebo (n = 6) or trametinib (n = 5). Survival was statistically evaluated using a log-rank (Mantel-Cox) test. When data are presented as boxplots, the box extends from the 25th to 75th percentiles, median is denoted by the internal line, and whiskers indicate the range calculated using the Tukey method, with data points outside the whiskers shown as individual points. All significant P values (P < 0.05) are noted in the figure.

Supplementary Materials

  • stm.sciencemag.org/cgi/content/full/11/490/eaat4822/DC1

    Fig. S1. Subcutaneous pump placement effect on survival.

    Fig. S2. Blood pressure effect in Fbn1mgR/mgR mice.

    Fig. S3. OR mRNA expression in the proximal ascending aorta.

    Fig. S4. Blood pressure effect in Fbn1mgR/mgR mice.

    Table S1. Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy and lactation in untreated mice.

    Table S2. Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy and lactation in treated mice.

    Table S3. Effect of OTA treatment on the average systolic and diastolic blood pressure.

    Table S4. Average OR expression in the aorta.

    Table S5. Effect of hydralazine or propranolol on the average systolic and diastolic blood pressure.

    Table S6. Average ERK1/2 phosphorylation in untreated mice.

    Table S7. Average ERK1/2 phosphorylation in treated mice.

    Table S8. Effect of trametinib on average systolic and diastolic blood pressure.

    Table S9. Average ERK1/2 phosphorylation in trametinib-treated mice.

  • This PDF file includes:

    • Fig. S1. Subcutaneous pump placement effect on survival.
    • Fig. S2. Blood pressure effect in Fbn1mgR/mgR mice.
    • Fig. S3. OR mRNA expression in the proximal ascending aorta.
    • Fig. S4. Blood pressure effect in Fbn1mgR/mgR mice.
    • Table S1. Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy and lactation in untreated mice.
    • Table S2. Average aortic root and ascending aortic growth over the 7-week period spanning pregnancy and lactation in treated mice.
    • Table S3. Effect of OTA treatment on the average systolic and diastolic blood pressure.
    • Table S4. Average OR expression in the aorta.
    • Table S5. Effect of hydralazine or propranolol on the average systolic and diastolic blood pressure.
    • Table S6. Average ERK1/2 phosphorylation in untreated mice.
    • Table S7. Average ERK1/2 phosphorylation in treated mice.
    • Table S8. Effect of trametinib on average systolic and diastolic blood pressure.
    • Table S9. Average ERK1/2 phosphorylation in trametinib-treated mice.

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