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 February 3, 2020; First 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 1

Col3a1G209S/+ and Col3a1G938D/+ mice recapitulate vEDS phenotypes.

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Col3a1G209S/+ and Col3a1G938D/+ mice recapitulate vEDS phenotypes. (A) ...
(A) Sanger sequencing of genomic DNA confirmed the intended Col3a1 c.625_626GG>TC corresponding to G209S. (B) Sanger sequencing of genomic DNA confirmed the intended Col3a1 c.2813G>A corresponding to G938D. (C) Kaplan-Meier survival curve for comparing Col3a1+/+ (n = 53) to Col3a1G209S/+ mice (n = 79), which died from vascular rupture or dissection. Significant differences were calculated using log-rank (Mantel-Cox) analysis. (D) Kaplan-Meier survival curve for comparing Col3a1+/+ (n = 78) to Col3a1G938D/+ mice (n = 51), which died from vascular rupture or dissection. Significant differences were calculated using log-rank (Mantel-Cox) analysis. (E) Quantification of collagen content in aortic cross sections, as measured by normalized PSR intensity. Error bars show mean ± SEM. Asterisks signify significant differences using 1-way ANOVA with Dunnett’s multiple comparisons post hoc test. ****P < 0.0001, DF = 2, F = 13.97. (F) Quantification of elastin breaks in VVG-stained aortic cross sections. Error bars show mean ± SEM. Asterisks signify significant differences using Kruskal-Wallis with Dunn’s multiple comparisons post hoc test. *P < 0.05, **P < 0.01. (G) Quantification of aortic wall thickness in aortic cross sections. Error bars show mean ± SEM. Asterisks signify significant differences using 1-way ANOVA with Dunnett’s multiple comparisons post hoc test. **P < 0.01, DF = 2, F = 10.16. (H) Histological staining (H&E = hematoxylin & eosin, VVG = Verhoeff Van Gieson, Masson’s Trichrome, and PSR = Picrosirius Red) of wild-type and vEDS aortic cross sections. Scale bars: 50 μm.