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First published online 30 August 2006
doi: 10.1242/dev.02538

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Man1, an inner nuclear membrane protein, regulates vascular remodeling by modulating transforming growth factor ß signaling

¹ The 21st Century Center of Excellence Program, Akita University School of Medicine, Hondo 1-1-1, Akita, Akita 010-8543, Japan.
² The J. David Gladstone Institutes, 1650 Owen Street, San Francisco, CA94158, USA.
³ Department of Biological Sciences, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
⁴ Department of Medicine and Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, 650 Charles E. Young Dr South, 47-123 CHS, Los Angeles, CA 90095, USA.

^* Author for correspondence (e-mail: osada{at}med.akita-u.ac.jp)

Accepted 18 July 2006

A growing number of integral inner nuclear membrane (INM) proteins have been implicated in diverse cellular functions. Man1, an INM protein, has recently been shown to regulate transforming growth factor (Tgf) ß superfamily signaling by interacting with receptor-associated Smads. However, the in vivo roles of Man1 have not been fully characterized. Here, we show that Man1 regulates vascular remodeling by analyzing Man1-deficient embryos lacking the Smad interacting domain. Man1-deficient embryos die at midgestation because of defects in embryonic vasculature; the primary capillary plexus forms, but subsequent remodeling is perturbed. It has been proposed that the angiogenesis process is divided into two balanced phases, the activation and resolution/maturation phases, both of which are regulated by Tgfß1. We have demonstrated, in Man1-deficient embryos, the expression of Tgfb1 is upregulated and Smad2/3 signaling is abnormally activated, resulting in increased extracellular matrix deposition, a hallmark of the resolution phase of angiogenesis. We have also showed that the recruitment of mural cells to the vascular wall is severely disturbed in mutants, which may lead to disruption of intercellular communication between endothelial and mural cells required for proper vascular remodeling. These results have revealed a novel role for Man1 in angiogenesis and provide the first evidence that vascular remodeling can be regulated at the INM through the interaction between Man1 and Smads.

Key words: Man1 (Lemd3), Inner nuclear membrane protein, Transforming growth factor ß signaling, Smad, Angiogenesis, Vascular remodeling, Xenopus, Mouse

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