Androgens Accentuate TGF-β Dependent Erk/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice

• Published in: Journal of the American Heart Association Vol. 9; no. 20; p. e015773
• Main Authors: Tashima, Yasushi, He, Hao, Cui, Jason Z, Pedroza, Albert J, Nakamura, Ken, Yokoyama, Nobu, Iosef, Cristiana, Burdon, Grayson, Koyano, Tiffany, Yamaguchi, Atsushi, Fischbein, Michael P
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 20.10.2020; Wiley
• Subjects: Androgen Antagonists - pharmacology; Androgens - metabolism; Androgens - pharmacology; aneurysm; Animals; Aortic Aneurysm, Thoracic - etiology; Aortic Aneurysm, Thoracic - metabolism; cell signaling; Dihydrotestosterone - metabolism; Dihydrotestosterone - pharmacology; Disease Progression; Flutamide - pharmacology; gender differences; Male; Marfan syndrome; Marfan Syndrome - complications; Matrix Metalloproteinase 2 - metabolism; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Organ Size; Original Research; Signal Transduction - drug effects; Smad2 Protein - metabolism; Transforming Growth Factor beta - metabolism; vascular biology; aneurysm; vascular biology; Marfan syndrome; gender differences; cell signaling
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.119.015773

Background Male patients with Marfan syndrome have a higher risk of aortic events and root dilatation compared with females. The role androgens play during Marfan syndrome aneurysm development in males remains unknown. We hypothesized that androgens potentiate transforming growth factor beta induced Erk (extracellular-signal-regulated kinase)/Smad activation, contributing to aneurysm progression in males. Methods and Results Aortic diameters in and littermate wild-type controls were measured at ages 6, 8, 12, and 16 weeks. males were treated with (1) flutamide (androgen receptor blocker) or (2) vehicle control from age 6 to 16 weeks and then euthanized. p-Erk1/2, p-Smad2, and matrix metalloproteinase (MMP) activity were measured in ascending/aortic root and descending aorta specimens. male and female ascending/aortic root-derived smooth muscle cells were utilized in vitro to measure Erk/Smad activation and MMP-2 activity following dihydrotestosterone, flutamide or transforming growth factor beta 1 treatment. males have increased aneurysm growth. p-Erk1/2 and p-Smad2 were elevated in ascending/aortic root specimens at age 16 weeks. Corresponding with enhanced Erk/Smad signaling, MMP-2 activity was higher in males. In vitro smooth muscle cell studies revealed that dihydrotestosterone potentiates transforming growth factor beta-induced Erk/Smad activation and MMP-2 activity, which is reversed by flutamide treatment. Finally, in vivo flutamide treatment reduced aneurysm growth via p-Erk1/2 and p-Smad2 reduction in males. Conclusions males have enhanced aneurysm growth compared with females associated with enhanced p-Erk1/2 and p-Smad2 activation. Mechanistically, in vitro smooth muscle cell studies suggested that dihydrotestosterone potentiates transforming growth factor beta induced Erk/Smad activation. As biological proof of concept, flutamide treatment attenuated aneurysm growth and p-Erk1/2 and p-Smad2 signaling in males.