Match!

Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome

Published on Dec 17, 2019in Journal of Clinical Investigation12.282
· DOI :10.1172/JCI130730
Caitlin J. Bowen (HHMI: Howard Hughes Medical Institute), Caitlin J. Bowen (HHMI: Howard Hughes Medical Institute)+ 6 AuthorsHarry C. Dietz90
Estimated H-index: 90
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-alpha 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 PKCbeta 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.
  • References (64)
  • Citations (0)
📖 Papers frequently viewed together
34 Citations
5 Citations
1 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References64
Newest
#1Helena Kuivaniemi (UCT: University of Cape Town)H-Index: 56
#2Gerard TrompH-Index: 56
Abstract Collagen alpha-1(III) chain, also known as the alpha 1 chain of type III collagen, is a protein that in humans is encoded by the COL3A1 gene. Three alpha 1 chains are required to form the type III collagen molecule which has a long triple-helical domain. Type III collagen, an extracellular matrix protein, is synthesized by cells as a pre-procollagen. It is found as a major structural component in hollow organs such as large blood vessels, uterus and bowel. Other functions of type III co...
1 CitationsSource
#1Jennifer Habashi (Johns Hopkins University)H-Index: 13
#2Elena Gallo MacFarlane (Johns Hopkins University)H-Index: 1
Last. Harry C. Dietz (Johns Hopkins University)H-Index: 90
view all 12 authors...
Women with Marfan syndrome (MFS) are at high risk for pregnancy-associated aortic dissection. Pathogenic models that singularly invoke hemodynamic stress are difficult to reconcile with predominant postnatal occurrence of aortic tear, often occurring weeks to months after delivery. In consideration of events that peak at term, are sustained after delivery, and might synergize with previously defined signaling pathways implicated in aneurysm progression, we examined the hormone oxytocin, which in...
1 CitationsSource
#1De Backer J (Ghent University Hospital)H-Index: 41
#2T De Backer (Ghent University Hospital)H-Index: 21
Source
#1Michael Frank (French Institute of Health and Medical Research)H-Index: 13
#2Salma Adham (Paris IV: Paris-Sorbonne University)H-Index: 1
Last. Xavier JeunemaitreH-Index: 69
view all 13 authors...
Abstract Background Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality. Objectives The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center. Methods All...
2 CitationsSource
#1Nicolo DubacherH-Index: 2
Last. Gabor Matyas (UZH: University of Zurich)H-Index: 20
view all 14 authors...
Source
#1A. Korneva (Yale University)H-Index: 2
#2Lior Zilberberg (NYU: New York University)H-Index: 13
Last. Chiara Bellini (NU: Northeastern University)H-Index: 10
view all 5 authors...
Fibrillin-1 is an elastin-associated glycoprotein that contributes to the long-term fatigue resistance of elastic fibers as well as to the bioavailability of transforming growth factor-beta (TGFβ) in arteries. Altered TGFβ bioavailability and/or signaling have been implicated in aneurysm development in Marfan syndrome (MFS), a multi-system condition resulting from mutations to the gene that encodes fibrillin-1. We recently showed that the absence of the latent transforming growth factor-beta bin...
2 CitationsSource
#2Sarah J. Parker (Johns Hopkins University)H-Index: 5
Last. Harry C. DietzH-Index: 90
view all 15 authors...
3 CitationsSource
#1Sanne D'hondt (UGent: Ghent University)H-Index: 4
#2Brecht Guillemyn (UGent: Ghent University)H-Index: 5
Last. Fransiska Malfait (UGent: Ghent University)H-Index: 35
view all 15 authors...
Abstract Type III collagen is a major fibrillar collagen consisting of three identical α1(III)-chains that is particularly present in tissues exhibiting elastic properties, such as the skin and the arterial wall. Heterozygous mutations in the COL3A1 gene result in vascular Ehlers-Danlos syndrome (vEDS), a severe, life-threatening disorder, characterized by thin, translucent skin and propensity to arterial, intestinal and uterine rupture. Most human vEDS cases result from a missense mutation subs...
7 CitationsSource
#1Nicola Chiarelli (University of Brescia)H-Index: 12
#2Giulia Carini (University of Brescia)H-Index: 3
Last. Marina Colombi (University of Brescia)H-Index: 20
view all 5 authors...
Vascular Ehlers-Danlos syndrome (vEDS) is a dominantly inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs. The majority of disease-causing variants in COL3A1 are glycine substitutions and in-frame splice mutations in the triple helix domain that through a dominant negative effect are associated with the severe clinical spectrum potentially lethal of vEDS, ch...
9 CitationsSource
#1Yasir Alsiraj (UK: University of Kentucky)H-Index: 3
#2Sean E. Thatcher (UK: University of Kentucky)H-Index: 15
Last. Lisa A. Cassis (UK: University of Kentucky)H-Index: 55
view all 6 authors...
Objective—Aortic pathologies exhibit sexual dimorphism, with aneurysms in both the thoracic and abdominal aorta (ie, abdominal aortic aneurysm [AAA]) exhibiting higher male prevalence. Women have lower prevalence of aneurysms, but when they occur, aneurysms progress rapidly. To define mechanisms for these sex differences, we determined the role of sex chromosome complement and testosterone on the location and progression of angiotensin II (AngII)–induced aortic pathologies. Approach and Results—...
8 CitationsSource
Cited By0
Newest