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 6

Inhibition of oxytocin signaling decreases ERK activation and ERK target gene expression.

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Inhibition of oxytocin signaling decreases ERK activation and ERK target...
(A) Representative Western blot analysis of pERK1/2 in the proximal descending aorta comparing Col3a1+/+ never-pregnant, Col3a1+/+ lactating, Col3a1G209S/+ never-pregnant, and Col3a1G209S/+ lactating mice, Col3a1G209S/+ mice with pups removed thereby preventing lactation, and Col3a1G209S/+ mice treated with trametinib (MEKi), oxytocin receptor antagonist (OTA), hydralazine, or propranolol. (B) Quantification of Western blot analysis of pERK1/2 in the proximal descending aorta in Col3a1+/+ never-pregnant (n = 5), Col3a1+/+ lactating (n = 5), Col3a1G209S/+ never-pregnant (n = 5), and Col3a1G209S/+ lactating mice (n = 5), Col3a1G209S/+ mice with pups removed thereby preventing lactation (n = 5), and Col3a1G209S/+ mice treated with trametinib (n = 5, MEKi), oxytocin receptor antagonist (n = 5, OTA), hydralazine (n = 3), or propranolol (n = 5). Error bars show mean ± SEM. Asterisks signify significant differences of log-transformed data using 1-way ANOVA with Dunnett’s multiple comparisons post hoc test. ***P < 0.001. DF = 8, F = 8.06. (C) qPCR analysis of Fos normalized to Gapdh in the proximal descending aorta comparing wild-type never-pregnant (n = 6, NP), wild-type lactating (n = 4, LAC), and Col3a1G209S/+ never-pregnant mice (n = 8, NP), Col3a1G209S/+ lactating mice (n = 10), and Col3a1G209S/+ mice treated with trametinib (n = 5, LAC + MEKi), oxytocin receptor antagonist (n = 4, LAC + OTA), or hydralazine (n = 3, LAC + hyd). Error bars show mean ± SEM. Asterisks signify significant differences of log-transformed data using 1-way ANOVA with Dunnett’s multiple comparisons post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001. DF = 6, F = 13.84. (D) qPCR analysis of Egr1 normalized to Gapdh in the proximal descending aorta comparing Col3a1+/+ never-pregnant (n = 10, NP), Col3a1+/+ lactating (n = 7, LAC), Col3a1G209S/+ never-pregnant (n = 5, NP), and Col3a1G209S/+ lactating mice (n = 10, LAC), and Col3a1G209S/+ mice treated with trametinib (n = 5, LAC + MEKi), oxytocin receptor antagonist (n = 4, LAC + OTA), or hydralazine (n = 3, LAC + hyd). Error bars show mean ± SEM. Asterisks signify significant differences using 1-way ANOVA with Dunnett’s multiple comparisons post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. DF = 6, F = 14.84.