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

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Research
• Connective Tissue Disorders

Background:

• Vascular Ehlers-Danlos syndrome (vEDS) is a severe genetic disorder characterized by arterial fragility.
• It stems from mutations in the COL3A1 gene, impacting collagen III production and extracellular matrix integrity.
• This leads to life-threatening complications like arterial dissection and rupture.

Purpose of the Study:

• To investigate the molecular mechanisms underlying vEDS vascular pathology.
• To identify potential therapeutic targets for vEDS.
• To explore the role of specific signaling pathways and hormonal influences in vEDS progression.

Main Methods:

• Development of two mouse models with heterozygous Col3a1 mutations mimicking human vEDS.
• Analysis of signaling pathways, including phospholipase C/inositol 1,4,5-triphosphate/protein kinase C/extracellular signal-regulated kinase (PLC/IP3/PKC/ERK).
• Pharmacological inhibition of ERK1/2 and PKCβ; modulation of oxytocin and androgen signaling.

Main Results:

• Signaling abnormalities in the PLC/IP3/PKC/ERK pathway were identified as key mediators of vascular damage in vEDS mice.
• Pharmacological inhibition of ERK1/2 or PKCβ significantly reduced mortality from aortic rupture.
• Attenuation of oxytocin and androgen signaling ameliorated pregnancy- and puberty-associated vascular risks, respectively.

Conclusions:

• Targetable signaling pathways, including PKC/ERK, are critical in vEDS pathogenesis.
• Pharmacological interventions targeting these pathways show promise for treating vEDS.
• Modulating hormonal signaling pathways may mitigate specific vEDS-related vascular risks.