Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart

Arita, Yoh; Nakaoka, Yoshikazu; Matsunaga, Taichi; Kidoya, Hiroyasu; Yamamizu, Kohei; Arima, Yuichiro; Kataoka-Hashimoto, Takahiro; Ikeoka, Kuniyasu; Yasui, Toshihiro; Tomita, Masaki; Yamamoto, Kaori; Higuchi, Kaori; Park, Jin-Sung; Shirai, Makoto; Nishiyama, Koichi; Yamagishi, Hiroyuki; Otsu, Kinya; Kurihara, Hiroki; Minami, Takashi; Yamauchi–Takihara, Keiko; Koh, Gou Young; Mochizuki, Naoki; Takakura, Nobuyuki; Sakata, Yasushi; Yamashita, Jun; Komuro, Issei

doi:10.1038/ncomms5552

Cited by 71 publications

(70 citation statements)

References 40 publications

(80 reference statements)

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“…Many studies and reviews in the past years have made valuable contributions to the ongoing debate on the origins of coronary vessels in the developing heart. [5][6][7][8]14,[23][24][25][26][27] A consensus has emerged that there are 3 important sources for coronary vessels: proepicardium, VE, and SV. [1][2][3][4]28 Each source represents a unique developmental origin that may determine different models of coronary vessels formation.…”

Section: Discussionmentioning

confidence: 99%

Endocardium Minimally Contributes to Coronary Endothelium in the Embryonic Ventricular Free Walls

Zhang

et al. 2016

Circulation Research

134

141

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Rationale: There is persistent uncertainty regarding the developmental origins of coronary vessels, with 2 principal sources suggested as ventricular endocardium or sinus venosus (SV). These 2 proposed origins implicate fundamentally distinct mechanisms of vessel formation. Resolution of this controversy is critical for deciphering the programs that result in the formation of coronary vessels and has implications for research on therapeutic angiogenesis. Objective: To resolve the controversy over the developmental origin of coronary vessels. Methods and Results: We first generated nuclear factor of activated T cells (Nfatc1)-Cre and Nfatc1-Dre lineage tracers for endocardium labeling. We found that Nfatc1 recombinases also label a significant portion of SV endothelial cells in addition to endocardium. Therefore, restricted endocardial lineage tracing requires a specific marker that distinguishes endocardium from SV. By single-cell gene expression analysis, we identified a novel endocardial gene natriuretic peptide receptor 3 (Npr3). Npr3 is expressed in the entirety of the endocardium but not in the SV. Genetic lineage tracing based on Npr3-CreER showed that endocardium contributes to a minority of coronary vessels in the free walls of embryonic heart. Intersectional genetic lineage tracing experiments demonstrated that endocardium minimally contributes to coronary endothelium in the embryonic ventricular free walls. Conclusions: Our study suggested that SV, but not endocardium, is the major origin for coronary endothelium in the embryonic ventricular free walls. This work thus resolves the recent controversy over the developmental origin of coronary endothelium, providing the basis for studying coronary vessel formation and regeneration after injury.

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Section: Discussionmentioning

confidence: 99%

Endocardium Minimally Contributes to Coronary Endothelium in the Embryonic Ventricular Free Walls

Zhang

et al. 2016

Circulation Research

134

141

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“…These findings led us to generate double Angpt1/Angpt2-deficient (A1:A2 (36,37) or Angpt2 fl/fl (38) mice with the ubiquitin-Cre-ER T2 mouse, depleted Angpt1 or Angpt2 starting at P1 by tamoxifen administration, and analyzed the tamoxifen-treated mice at P14 (Supplemental SCs compared with those of WT (Figure 7, A-G). Moreover, the A1:A2 iΔ/Δ mice had scant GVs, thinned RNFL, and markedly attenuated pSTR and PhNR ( Figure 8, A-H), results similar to those of a previous report (26).…”

Section: Tie2 Expression Precedes Prox1 Expression In the Scmentioning

confidence: 99%

Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma

Kim¹,

Park

Bae³

et al. 2017

Journal of Clinical Investigation

104

137

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“…For the immunohistochemical analyses of murine lung tissues, samples were fixed in 4% PFA/PBS for 1 h, cryoprotected with PBS containing 5-20% sucrose, frozen in OCT compound (Sakura), and cut into 10-μm-thick cryosections as described previously (46). Human lung samples, which were formaldehydefixed and paraffin-embedded, were cut into 5-μm-thick sections, deparaffinized, and rehydrated.…”

Section: Histological and Immunohistochemical Analyses Of The Pulmonamentioning

confidence: 99%

Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension

Hashimoto-Kataoka¹,

Hosen²,

Sonobe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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189

157

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IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxiainduced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.pulmonary arterial hypertension | interleukin-21 | interleukin-6 | Th17 cells | M2 macrophage

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Myocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart

Cited by 71 publications

References 40 publications

Endocardium Minimally Contributes to Coronary Endothelium in the Embryonic Ventricular Free Walls

Endocardium Minimally Contributes to Coronary Endothelium in the Embryonic Ventricular Free Walls

Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma

Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension

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