Atrial natriuretic peptide (ANP) is a cardiac hormone released by the atrium in response to stretching forces. Via its receptor, guanylyl cyclase-A (GC-A), ANP maintains cardiovascular homeostasis by exerting diuretic, natriuretic, and hypotensive effects mediated, in part, by endothelial cells. Both in vivo and in vitro, ANP enhances endothelial barrier function by reducing RhoA activity and reorganizing the actin cytoskeleton. We established mouse endothelial cells that stably express GC-A and used them to analyze the molecular mechanisms responsible for actin reorganization. Stimulation by ANP resulted in phosphorylation of myosin light chain (MLC) and promotion of cell spreading. p21-activated kinase 4 (PAK4) and cerebral cavernous malformations 2 (CCM2), a scaffold protein involved in a cerebrovascular disease, were required for the phosphorylation of MLC and promotion of cell spreading by ANP. Finally, in addition to the GC domain, the kinase homology domain of GC-A was also required for ANP/GC-A signaling. Our results indicate that CCM2 and PAK4 are important downstream mediators of ANP/GC-A signaling involved in cell spreading, an important initial step in the enhancement of endothelial barrier function.
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Atrial natriuretic peptide (ANP) is a cardiac hormone released by the atrium in response to stretching forces. ANP, which maintains cardiovascular homeostasis via its diuretic, natriuretic and hypotensive effects, acts through its receptor, GC-A. In this issue of the Biochemical Journal, Miura et al. (pages 1897–1918) established mouse immortalized endothelial cells stably expressing GC-A (SVEC/GC-A) and found that ANP promotes cell spreading and endothelial barrier function via regulation of CCM2, an adaptor protein involved in the pathogenesis of cerebral cavernous malformations, a neurovascular disease characterized by dysfunction of the endothelial barrier. The image shows ANP promotes co-localization of GC-A (green) and CCM2 (red) at membrane ruffles in SVEC/GC-A. Image kindly provided by Koichi Miura
CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading
Koichi Miura, Takashi Nojiri, Yoshiharu Akitake, Koji Ando, Shigetomo Fukuhara, Masahiro Zenitani, Toru Kimura, Jun Hino, Mikiya Miyazato, Hiroshi Hosoda, Kenji Kangawa; CCM2 and PAK4 act downstream of atrial natriuretic peptide signaling to promote cell spreading. Biochem J 1 June 2017; 474 (11): 1897–1918. doi: https://doi.org/10.1042/BCJ20160841
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