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.
View: Text | PDF
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

×

Figure 4

Androgen signaling at puberty increases the risk of aortic rupture.

Options: View larger image (or click on image) Download as PowerPoint
Androgen signaling at puberty increases the risk of aortic rupture. (A) ...
(A) Kaplan-Meier survival curve comparing Col3a1G938D/+ (n = 51) to Col3a1G938D/+ (n = 41) mice receiving hydralazine from birth. (B) Kaplan-Meier survival curve comparing female Col3a1G938D/+ (n = 24) to female Col3a1G938D/+ (n = 23) mice receiving hydralazine starting from birth and bicalutamide starting from weaning (n = 9). P values shown are between untreated mice and mice receiving hydralazine (lower) and mice receiving hydralazine and mice receiving hydralazine and bicalutamide (upper). (C) Kaplan-Meier survival curve comparing male Col3a1G938D/+ (n = 27) to male Col3a1G938D/+ mice receiving hydralazine starting from birth (n = 18) and male Col3a1G938D/+ mice receiving hydralazine starting from birth and bicalutamide starting from weaning and continuing for 2 months (n = 18). P values shown are between untreated mice and mice receiving hydralazine (lower) and mice receiving hydralazine and mice receiving hydralazine and bicalutamide (upper). (D) Kaplan-Meier survival curve comparing Col3a1G938D/+ (n = 93) mice to Col3a1G938D/+ mice receiving bicalutamide (n = 20). (E) Kaplan-Meier survival curve comparing Col3a1G938D/+ (n = 93) mice to Col3a1G938D/+ mice receiving hydralazine and spironolactone (n = 16). (F) Representative Western blot analysis of pERK comparing Col3a1+/+ (n = 9) to Col3a1G938D/+ (n = 7) mice, Col3a1G938D/+ mice on hydralazine sampled at age P40 (Hydral (E), n = 5), Col3a1G938D/+ mice on hydralazine and spironolactone sampled at age P70 (Hydral (L)+spiro, n = 5), and Col3a1G938D/+ mice on hydralazine sampled at age P70 (Hydral (L), n = 5) proximal descending aortas. (G) Quantification of pERK levels normalized to β-actin–loading control for 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 < 0.05, DF = 4, F = 7.07. For all survival curves, significant differences were calculated using log-rank (Mantel-Cox) analysis. P0, postnatal day 0; P21, postnatal day 21; hydral, hydralazine; bical, bicalutamide; spiro, spironolactone. All findings from drug trials are based on analyses using a control group with n = 93 across all drug tests. FDR-adjusted P values are presented in Supplemental Table 3.