TY - JOUR
T1 - Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome
AU - Bowen, Caitlin J.
AU - Giadrosic, Juan Francisco Calderón
AU - Burger, Zachary
AU - Rykiel, Graham
AU - Davis, Elaine C.
AU - Helmers, Mark R.
AU - Benke, Kelly
AU - MacFarlane, Elena Gallo
AU - Dietz, Harry C.
N1 - Funding Information:
We thank the staff of the Next Generation Sequencing Center, Research Animal Resources, and the Transgenic Core Laboratory at Johns Hopkins University School of Medicine for their assistance with various aspects of this project. We thank Jennifer Habashi and Djahida Bedja (Johns Hopkins University) for their assistance with echocardiograms and Maurice Manning (University of Toledo) for providing the oxytocin receptor antagonist and guidance regarding its use in animal studies. Supported by grants from the NIH (AR41135 to HCD; GM007309 to CJB), the Howard Hughes Medical Institute (to HCD), the Marfan Foundation (to HCD), the Ehlers Danlos Syndrome Network C.A.R.E.S. Foundation (to HCD), EDS Today (to HCD), the Daskal Family Foundation (to HCD), the Alison Aldredge Family Foundation (to HCD), the DEFY Foundation (to HCD), the Natural Sciences and Engineering Research Council of Canada (to ECD), the Fulbright-Conicyt Scholarship (to JFCG), and Fondecyt Grant (11170353 to JFCG).
PY - 2020/2/3
Y1 - 2020/2/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI130730
DO - 10.1172/JCI130730
M3 - Article
C2 - 31639107
AN - SCOPUS:85078868498
VL - 130
SP - 686
EP - 698
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 2
ER -