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Impact of Notch3 Activation on Aortic Aneurysm Development in Marfan Syndrome

Kathryn Jespersen1, Chenxin Li2, Rishi Batra1

  • 1Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-7690, USA.

Journal of Immunology Research
|February 25, 2022
PubMed
Abstract

Insights

In Marfan syndrome (MFS), increased Notch3 activation contributes to aortic aneurysm by altering smooth muscle cells. Inhibiting Notch3 may offer a new treatment strategy for MFS aortic disease.

Area of Science:

  • Vascular Biology
  • Connective Tissue Disorders
  • Molecular Signaling

Background:

  • Thoracic aortic aneurysm and dissection are leading causes of mortality in Marfan syndrome (MFS).
  • Notch signaling is crucial for blood vessel development and function.
  • The precise role of Notch signaling in MFS aortic pathology and smooth muscle cell (SMC) differentiation remains unclear.

Purpose of the Study:

  • To investigate the role of Notch signaling in the pathogenesis of aortic aneurysms in Marfan syndrome.
  • To determine the effect of Notch3 activation on aortic smooth muscle cell differentiation in MFS.
  • To evaluate the therapeutic potential of inhibiting Notch activation in MFS-associated aortic disease.

Main Methods:

  • RNA-sequencing of ascending aortic tissue from a mouse model of MFS (Fbn1) and wild-type controls.
  • Confirmation of Notch 3 expression and activation using RT-PCR, immunohistochemistry, and Western blot.
  • Pharmacological inhibition of Notch activation with a gamma-secretase inhibitor (DAPT) in mice, followed by evaluation of aortic pathology and survival.

Main Results:

  • Elevated Notch3 activation was observed in the aortic tissue of MFS mice and humans.
  • Increased Notch3 activation correlated with enhanced expression of SMC contractile markers.
  • DAPT treatment attenuated aortic enlargement, reduced elastin fragmentation, reversed SMC differentiation, and improved survival in Fbn1 mice.

Conclusions:

  • Matrix abnormalities in MFS aortas are associated with heightened Notch3 activation.
  • Enhanced Notch3 activation contributes to aortic aneurysm formation in MFS, potentially by inducing SMC phenotypic changes.
  • Inhibiting Notch3 activation presents a potential therapeutic strategy for preventing and treating aortic aneurysms in Marfan syndrome.

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