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 3

Inhibition of excessive PKCβ or ERK signaling prevents death due to aortic dissection.

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Inhibition of excessive PKCβ or ERK signaling prevents death due to aort...
(A) Kaplan-Meier survival curve comparing Col3a1G938D/+ (n = 93) to Col3a1G938D/+ (n = 16) mice receiving ruboxistaurin in the diet starting at weaning and continuing for 40 days. Significant differences were calculated using log-rank (Mantel-Cox) analysis. P21 = postnatal day 21. (B) Representative Western blot and analysis of pPKCβ and pERK comparing Col3a1+/+ (n = 6) to Col3a1G938D/+ (n = 6) proximal descending aortas and quantification of pPKCβ and pERK levels normalized to β-actin loading control for vEDS aortas. Error bars show mean ± SEM. Asterisks signify significant differences using 1-way ANOVA with Dunnett’s multiple comparisons post hoc test. **P < 0.01, ***P < 0.001, DF = 3, F = 13. (C) Kaplan-Meier survival curve comparing Col3a1G938D/+ (n = 93) to Col3a1G938D/+ (n = 20) mice receiving cobimetinib in the drinking water starting at weaning and continuing for 40 days. Significant differences were calculated using log-rank (Mantel-Cox) analysis. P21 = postnatal day 21. All findings from drug trials are based on analyses using a universal control group with n = 93 across all drug tests that started at P21. FDR-adjusted P values are presented in Supplemental Table 3.