title: BMP type I receptor inhibition attenuates endothelial dysfunction in mice with chronic kidney disease.
abstract: The molecular mechanisms of endothelial dysfunction and vascular calcification have been considered independently and potential links are currently unknown in chronic kidney disease (CKD). Bone morphogenetic protein (BMP) receptor signaling mediates calcification of atherosclerotic plaques. Here we tested whether BMP receptor signaling contributes to endothelial dysfunction, as well as to osteogenic differentiation of vascular smooth muscle cells (VSMCs), in a model of short-term CKD. In C57BL/6 mice, subtotal nephrectomy activated BMP receptor and increased phosphatase-and-tensin homolog (PTEN) protein in the endothelial cells and medial VSMCs without vascular remodeling in the aorta. In the endothelial cells, PTEN induction led to inhibition of the Akt-endothelial nitric oxide synthase (eNOS) pathway and endothelial dysfunction. In VSMCs, the PTEN increase induced early osteogenic differentiation. CKD-induced inhibition of eNOS phosphorylation and the resultant endothelial dysfunction were inhibited in mice with endothelial cell-specific PTEN ablation. Knockout of the BMP type I receptor abolished endothelial dysfunction, the inhibition of eNOS phosphorylation, and VSMC osteogenic differentiation in mice with CKD. A small molecule inhibitor of BMP type I receptor, LDN-193189, prevented endothelial dysfunction and osteogenic differentiation in CKD mice. Thus, BMP receptor activation is a mechanism for endothelial dysfunction in addition to vascular osteogenic differentiation in a short-term CKD model. PTEN may be key in linking BMP receptor activation and endothelial dysfunction in CKD.
authors: Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
authors: Hidemi
authors: H
authors: Kajimoto
authors: Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
authors: Hisashi
authors: H
authors: Kai
authors: Cardiovascular Research Institute, Kurume University, Kurume, Japan.
authors: Hiroki
authors: H
authors: Aoki
authors: Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
authors: Hiroki
authors: H
authors: Uchiwa
authors: Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
authors: Yuji
authors: Y
authors: Aoki
authors: Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
authors: Suguru
authors: S
authors: Yasuoka
authors: Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
authors: Takahiro
authors: T
authors: Anegawa
authors: Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA.
authors: Yuji
authors: Y
authors: Mishina
authors: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors: Akira
authors: A
authors: Suzuki
authors: Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan.
authors: Yoshihiro
authors: Y
authors: Fukumoto
authors: 1] Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University, Kurume, Japan [2] International University of Health and Welfare/Fukuoka Sanno Hospital, Fukuoka, Japan.
authors: Tsutomu
authors: T
authors: Imaizumi
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors* / Q000502:physiology*; D042783:Endothelial Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D010012:Osteogenesis; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*
chemical_list: D052250:Nitric Oxide Synthase Type III; D052005:Bone Morphogenetic Protein Receptors, Type I