Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome
Caitlin J. Bowen, … , Elena Gallo MacFarlane, Harry C. Dietz
Caitlin J. Bowen, … , Elena Gallo MacFarlane, Harry C. Dietz
Published October 22, 2019
Citation Information: J Clin Invest. 2020;130(2):686-698. https://doi.org/10.1172/JCI130730.
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Research Article Cardiology Vascular biology

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome

Abstract

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal-dominant connective tissue disorder caused by heterozygous mutations in the COL3A1 gene, which encodes the pro-α 1 chain of collagen III. Loss of structural integrity of the extracellular matrix is believed to drive the signs and symptoms of this condition, including spontaneous arterial dissection and/or rupture, the major cause of mortality. We created 2 mouse models of vEDS that carry heterozygous mutations in Col3a1 that encode glycine substitutions analogous to those found in patients, and we showed that signaling abnormalities in the PLC/IP3/PKC/ERK pathway (phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal–regulated kinase) are major mediators of vascular pathology. Treatment with pharmacologic inhibitors of ERK1/2 or PKCβ prevented death due to spontaneous aortic rupture. Additionally, we found that pregnancy- and puberty-associated accentuation of vascular risk, also seen in vEDS patients, was rescued by attenuation of oxytocin and androgen signaling, respectively. Taken together, our results provide evidence that targetable signaling abnormalities contribute to the pathogenesis of vEDS, highlighting unanticipated therapeutic opportunities.

Authors

Caitlin J. Bowen, Juan Francisco Calderón Giadrosic, Zachary Burger, Graham Rykiel, Elaine C. Davis, Mark R. Helmers, Kelly Benke, Elena Gallo MacFarlane, Harry C. Dietz

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Figure 5

Oxytocin signaling during lactation increases the risk of aortic rupture.

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Oxytocin signaling during lactation increases the risk of aortic rupture...
(A) Kaplan-Meier survival curve for lactating Col3a1G209S/+ mice (n = 22) compared with never-pregnant female (n = 55) Col3a1G209S/+ mice. (B) Kaplan-Meier survival curve comparing Col3a1G209S/+ lactating (n = 22) mice to Col3a1G209S/+ females with pups removed on the day of delivery thereby preventing lactation and eliminating the lactation-induced prolonged elevation of oxytocin (n = 13). (C) Kaplan-Meier survival curve comparing Col3a1G209S/+ lactating mice (n = 22) to Col3a1G209S/+ females with oxytocin receptor antagonist (OTA) administered via a continuous subcutaneous infusion pump implanted at the end of the third week of gestation and continued through the 4 weeks of lactation, for a total of 5 weeks of treatment (n = 10). (D) Kaplan-Meier curve demonstrating the survival of Col3a1G209S/+ lactating mice treated with trametinib (n = 21), a MEK inhibitor, initiated at the start of the third week of pregnancy and continued through 4 weeks of lactation, in comparison to untreated lactating Col3a1G209S/+ mice (n = 22). (E) Kaplan-Meier curve demonstrating the survival of Col3a1G209S/+ lactating mice treated with hydralazine (n = 23) initiated at the start of the third week of pregnancy and continued through 4 weeks of lactation, in comparison to lactating untreated Col3a1G209S/+ mice (n = 22). (F) Kaplan-Meier curve demonstrating the survival of Col3a1G209S/+ lactating mice treated with propranolol (n = 8), initiated at the start of the third week of pregnancy and continued through 4 weeks of lactation, in comparison to lactating untreated Col3a1G209S/+ mice (n = 22). For all survival curves, significant differences were calculated using log-rank (Mantel-Cox) analysis, and controls are pooled analyses of n = 22 mice. FDR-adjusted P values are presented in Supplemental Table 3.