Angpt1 binding to Tie1 regulates the signaling required for lymphatic vessel development in zebrafish.

Development of the vascular system is regulated by multiple signaling pathways mediated by receptor tyrosine kinases. Among them, angiopoietin (Ang)/Tie signaling regulates lymphatic and blood vessel development in mammals. Of the two Tie receptors, Tie2 is well known as a key mediator of Ang/Tie signaling, but, unexpectedly, recent studies have revealed that the Tie2 locus has been lost in many vertebrate species, whereas the Tie1 gene is more commonly present. However, Tie1-driven signaling pathways, including ligands and cellular functions, are not well understood. Here, we performed comprehensive mutant analyses of angiopoietins and Tie receptors in zebrafish and found that only angpt1 and tie1 mutants show defects in trunk lymphatic vessel development. Among zebrafish angiopoietins, only Angpt1 binds to Tie1 as a ligand. We indirectly monitored Ang1/Tie1 signaling and detected Tie1 activation in sprouting endothelial cells, where Tie1 inhibits nuclear import of EGFP-Foxo1a. Angpt1/Tie1 signaling functions in endothelial cell migration and proliferation, and in lymphatic specification during early lymphangiogenesis, at least in part by modulating Vegfc/Vegfr3 signaling. Thus, we show that Angpt1/Tie1 signaling constitutes an essential signaling pathway for lymphatic development in zebrafish.

Heterogeneous pdgfrb+ cells regulate coronary vessel development and revascularization during heart regeneration.

Endothelial cells emerge from the atrioventricular canal to form coronary blood vessels in juvenile zebrafish hearts. We find that pdgfrb is first expressed in the epicardium around the atrioventricular canal and later becomes localized mainly in the mural cells. pdgfrb mutant fish show severe defects in mural cell recruitment and coronary vessel development. Single-cell RNA sequencing analyses identified pdgfrb+ cells as epicardium-derived cells (EPDCs) and mural cells. Mural cells associated with coronary arteries also express cxcl12b and smooth muscle cell markers. Interestingly, these mural cells remain associated with coronary arteries even in the absence of Pdgfrß, although smooth muscle gene expression is downregulated. We find that pdgfrb expression dynamically changes in EPDCs of regenerating hearts. Differential gene expression analyses of pdgfrb+ EPDCs and mural cells suggest that they express genes that are important for regeneration after heart injuries. mdka was identified as a highly upregulated gene in pdgfrb+ cells during heart regeneration. However, pdgfrb but not mdka mutants show defects in heart regeneration after amputation. Our results demonstrate that heterogeneous pdgfrb+ cells are essential for coronary development and heart regeneration.

Cardiac forces regulate zebrafish heart valve delamination by modulating Nfat signaling.

In the clinic, most cases of congenital heart valve defects are thought to arise through errors that occur after the endothelial-mesenchymal transition (EndoMT) stage of valve development. Although mechanical forces caused by heartbeat are essential modulators of cardiovascular development, their role in these later developmental events is poorly understood. To address this question, we used the zebrafish superior atrioventricular valve (AV) as a model. We found that cellularized cushions of the superior atrioventricular canal (AVC) morph into valve leaflets via mesenchymal-endothelial transition (MEndoT) and tissue sheet delamination. Defects in delamination result in thickened, hyperplastic valves, and reduced heart function. Mechanical, chemical, and genetic perturbation of cardiac forces showed that mechanical stimuli are important regulators of valve delamination. Mechanistically, we show that forces modulate Nfatc activity to control delamination. Together, our results establish the cellular and molecular signature of cardiac valve delamination in vivo and demonstrate the continuous regulatory role of mechanical forces and blood flow during valve formation.

RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells.

During angiogenesis, VEGF acts as an attractive cue for endothelial cells (ECs), while Sema3E mediates repulsive cues. Here, we show that the small GTPase RhoJ integrates these opposing signals in directional EC migration. In the GTP-bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1-bound RhoJ further facilitates Sema3E-induced PlexinD1-VEGFR2 association, VEGFR2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, thereby preventing degradation of internalized VEGFR2, prolonging downstream signal transductions via PLCγ, Erk, and Akt, and promoting forward EC migration. After conversion to the GDP-bound state, RhoJ shifts from PlexinD1 to VEGFR2, which then terminates the VEGFR2 signals. RhoJ deficiency in ECs efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTPases may act as context-dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.

Rap1 small GTPase is essential for maintaining pulmonary endothelial barrier function in mice.

Vascular permeability is dynamically but tightly controlled by vascular endothelial (VE)-cadherin-mediated endothelial cell-cell junctions to maintain homeostasis. Thus, impairments of VE-cadherin-mediated cell adhesions lead to hyperpermeability, promoting the development and progression of various disease processes. Notably, the lungs are a highly vulnerable organ wherein pulmonary inflammation and infection result in vascular leakage. Herein, we showed that Rap1, a small GTPase, plays an essential role for maintaining pulmonary endothelial barrier function in mice. Endothelial cell-specific Rap1a/Rap1b double knockout mice exhibited severe pulmonary edema. They also showed vascular leakage in the hearts, but not in the brains. En face analyses of the pulmonary arteries and 3D-immunofluorescence analyses of the lungs revealed that Rap1 potentiates VE-cadherin-mediated endothelial cell-cell junctions through dynamic actin cytoskeleton reorganization. Rap1 inhibits formation of cytoplasmic actin bundles perpendicularly binding VE-cadherin adhesions through inhibition of a Rho-ROCK pathway-induced activation of cytoplasmic nonmuscle myosin II (NM-II). Simultaneously, Rap1 induces junctional NM-II activation to create circumferential actin bundles, which anchor and stabilize VE-cadherin at cell-cell junctions. We also showed that the mice carrying only one allele of either Rap1a or Rap1b out of the two Rap1 genes are more vulnerable to lipopolysaccharide (LPS)-induced pulmonary vascular leakage than wild-type mice, while activation of Rap1 by administration of 007, an activator for Epac, attenuates LPS-induced increase in pulmonary endothelial permeability in wild-type mice. Thus, we demonstrate that Rap1 plays an essential role for maintaining pulmonary endothelial barrier functions under physiological conditions and provides protection against inflammation-induced pulmonary vascular leakage.

A molecular atlas of cell types and zonation in the brain vasculature.

Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.

Author Correction: A molecular atlas of cell types and zonation in the brain vasculature.

In Fig. 1b of this Article, 'Csf1r' was misspelt 'Csfr1'. In addition, in Extended Data Fig. 11b, owing to an error during figure formatting, the genes listed in the first column shifted down three rows below the first gene on the list, causing a mismatch between the gene names and their characteristics. These errors have been corrected online, and the original Extended Data Fig. 11b is provided as Supplementary Information to the accompanying Amendment.

Cellular and humoral immune responses to COVID-19 booster vaccination in Japanese dialysis patients.

BACKGROUND: Dialysis patients are susceptible to developing severe coronavirus disease 2019 (COVID-19) due to hypoimmunity. Antibody titers against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) after the primary vaccinations are lower in hemodialysis (HD) patients than in healthy individuals. This study aimed to evaluate the effect of a SARS-CoV-2 booster vaccination in HD and peritoneal dialysis (PD) patients based on antibody titers and cellular and humoral immunity. METHODS: Participants of the control, HD, and PD groups were recruited from 12 facilities. SARS-CoV-2 antigen-specific cytokine and IgG-antibody levels were measured. Regulatory T cells and memory B cells were counted using flow cytometry at 6 months after primary vaccination with BNT162b2 and 3 weeks after the booster vaccination in HD and PD patients and compared with those of a control group. RESULTS: Booster vaccination significantly enhanced the levels of antibodies, cytokines, and memory B cells in three groups. The HD group showed significantly higher levels of IgG-antibodies, IL-1ß, IL-2, IL-4, IL-17, and memory B cells than those in the control group at 3 weeks after the booster dose. The PD group tended to show similar trends to HD patients but had similar levels of IgG-antibodies, cytokines, and memory B cells to the control group. CONCLUSIONS: HD patients had significantly stronger cellular and humoral immune responses than the control 3 weeks after the booster dose. Our findings will help in developing better COVID-19 vaccination strategies for HD and PD patients.

Conserved and context-dependent roles for pdgfrb signaling during zebrafish vascular mural cell development.

Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle cells. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these zebrafish mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects.

Peri-arterial specification of vascular mural cells from naïve mesenchyme requires Notch signaling.

Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naïve pdgfrblow mesenchymal cells. The emergence of peri-arterial pdgfrbhigh MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrbhigh MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrbhigh MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.

Osteocrin, a bone-derived humoral factor, exerts a renoprotective role in ischemia-reperfusion injury in mice.

BACKGROUND: Osteocrin (OSTN), a bone-derived humoral factor, was reported to act on heart and bone by potentiating the natriuretic peptide (NP) system. Ostn gene polymorphisms have been associated with renal function decline, but its pathophysiological role in the kidney remains unclear. METHODS: The role of endogenous OSTN was investigated using systemic Ostn-knockout (KO) mice. As a model for OSTN administration, liver-specific Ostn-overexpressing mice crossed with KO (KO-Tg) were generated. These mice were subjected to unilateral ischemia-reperfusion injury (IRI) and renal lesions after 21 days of insult were evaluated. A comprehensive analysis of the Wnt/ß-catenin pathway was performed using a polymerase chain reaction (PCR) array. Reporter plasmid-transfected proximal tubular cells (NRK52E) were used to investigate the mechanism by which OSTN affects the pathway. RESULTS: After injury, KO mice showed marginal worsening of renal fibrosis compared with wild-type mice, with comparable renal atrophy. KO-Tg mice showed significantly ameliorated renal atrophy, fibrosis and tubular injury, together with reduced expressions of fibrosis- and inflammation-related genes. The PCR array showed that the activation of the Wnt/ß-catenin pathway was attenuated in KO-Tg mice. The downstream targets Mmp7, Myc and Axin2 showed similar results. MMP7 and Wnt2 were induced in corticomedullary proximal tubules after injury, but not in KO-Tg. In NRK52E, OSTN significantly potentiated the inhibitory effects of NP on transforming growth factor ß1-induced activation of the Wnt/ß-catenin pathway, which was reproduced by a cyclic guanosine monophosphate analog. CONCLUSIONS: Ectopic Ostn overexpression ameliorated subsequent renal injury following ischemia-reperfusion. OSTN could represent possible renoprotection in acute to chronic kidney disease transition, thus serving as a potential therapeutic strategy.

In vivo analysis of cardiomyocyte proliferation during trabeculation.

Cardiomyocyte proliferation is crucial for cardiac growth, patterning and regeneration; however, few studies have investigated the behavior of dividing cardiomyocytes in vivo Here, we use time-lapse imaging of beating hearts in combination with the FUCCI system to monitor the behavior of proliferating cardiomyocytes in developing zebrafish. Confirming in vitro observations, sarcomere disassembly, as well as changes in cell shape and volume, precede cardiomyocyte cytokinesis. Notably, cardiomyocytes in zebrafish embryos and young larvae mostly divide parallel to the myocardial wall in both the compact and trabecular layers, and cardiomyocyte proliferation is more frequent in the trabecular layer. While analyzing known regulators of cardiomyocyte proliferation, we observed that the Nrg/ErbB2 and TGFß signaling pathways differentially affect compact and trabecular layer cardiomyocytes, indicating that distinct mechanisms drive proliferation in these two layers. In summary, our data indicate that, in zebrafish, cardiomyocyte proliferation is essential for trabecular growth, but not initiation, and set the stage to further investigate the cellular and molecular mechanisms driving cardiomyocyte proliferation in vivo.

Osteocrin, a peptide secreted from the heart and other tissues, contributes to cranial osteogenesis and chondrogenesis in zebrafish.

The heart is an endocrine organ, as cardiomyocytes (CMs) secrete natriuretic peptide (NP) hormones. Since the discovery of NPs, no other peptide hormones that affect remote organs have been identified from the heart. We identified osteocrin (Ostn) as an osteogenesis/chondrogenesis regulatory hormone secreted from CMs in zebrafish. ostn mutant larvae exhibit impaired membranous and chondral bone formation. The impaired bones were recovered by CM-specific overexpression of OSTN. We analyzed the parasphenoid (ps) as a representative of membranous bones. In the shortened ps of ostn morphants, nuclear Yap1/Wwtr1-dependent transcription was increased, suggesting that Ostn might induce the nuclear export of Yap1/Wwtr1 in osteoblasts. Although OSTN is proposed to bind to NPR3 (clearance receptor for NPs) to enhance the binding of NPs to NPR1 or NPR2, OSTN enhanced C-type NP (CNP)-dependent nuclear export of YAP1/WWTR1 of cultured mouse osteoblasts stimulated with saturable CNP. OSTN might therefore activate unidentified receptors that augment protein kinase G signaling mediated by a CNP-NPR2 signaling axis. These data demonstrate that Ostn secreted from the heart contributes to bone formation as an endocrine hormone.

A New Secretory Peptide of Natriuretic Peptide Family, Osteocrin, Suppresses the Progression of Congestive Heart Failure After Myocardial Infarction.

RATIONALE: An increase of severe ischemic heart diseases results in an increase of the patients with congestive heart failure (CHF). Therefore, new therapies are expected in addition to recanalization of coronary arteries. Previous clinical trials using natriuretic peptides (NPs) prove the improvement of CHF by NPs. OBJECTIVE: We aimed at investigating whether OSTN (osteocrin) peptide potentially functioning as an NPR (NP clearance receptor) 3-blocking peptide can be used as a new therapeutic peptide for treating CHF after myocardial infarction (MI) using animal models. METHODS AND RESULTS: We examined the effect of OSTN on circulation using 2 mouse models; the continuous intravenous infusion of OSTN after MI and the OSTN-transgenic (Tg) mice with MI. In vitro studies revealed that OSTN competitively bound to NPR3 with atrial NP. In both OSTN-continuous intravenous infusion model and OSTN-Tg model, acute inflammation within the first week after MI was reduced. Moreover, both models showed the improvement of prognosis at 28 days after MI by OSTN. Consistent with the in vitro study binding of OSTN to NPR3, the OSTN-Tg exhibited an increased plasma atrial NP and C-type NP, which might result in the improvement of CHF after MI as indicated by the reduced weight of hearts and lungs and by the reduced fibrosis. CONCLUSIONS: OSTN might suppress the worsening of CHF after MI by inhibiting clearance of NP family peptides.

Direct enantioseparation of mandelic acid by high-performance liquid chromatography using a phenyl column precoated with a small amount of cyclodextrin additive in a mobile phase.

Direct enantioseparation of mandelic acid by high-performance liquid chromatography (HPLC) with a reversed phase column and a mobile phase containing a small amount of hydroxylpropyl-ß-cyclodextrin (HP-ß-CD) was studied as an efficient method for saving consumption of the CD additive. As a result, it was proposed that racemic mandelic acid can be analyzed with a phenyl column by using a mobile phase composed of 10 mM ammonium acetate buffer (pH 4.2) and 0.02% (w/v) HP-ß-CD at a flow rate of 1.0 mL/min at 40°C after the passage of 10 mM ammonium acetate buffer (pH 4.2) containing 0.1% (w/v) HP-ß-CD as a precoating mobile phase for 60 min. It is suggested that HP-ß-CD is bound with a phenyl group on the surface of the stationary phase to allow a phenyl column to act as a transient chiral column, and injected mandelic acid can form the ternary complex with the adsorbed HP-ß-CD. The longer retention time of D-mandelic acid than the L-isomer for HPLC can be explained from the higher stability of the HP-ß-CD complex with D-mandelic acid, which was confirmed by CE experiment with HP-ß-CD as a selector. The efficiency of a phenyl column compared with other stationary phases was also discussed.

Live imaging of angiogenesis during cutaneous wound healing in adult zebrafish.

Angiogenesis, the growth of new blood vessels from pre-existing vessels, is critical for cutaneous wound healing. However, it remains elusive how endothelial cells (ECs) and pericytes (PCs) establish new blood vessels during cutaneous angiogenesis. We set up a live-imaging system to analyze cutaneous angiogenesis in adult zebrafish. First, we characterized basic structures of cutaneous vasculature. In normal skin tissues, ECs and PCs remained dormant to maintain quiescent blood vessels, whereas cutaneous injury immediately induced angiogenesis through the vascular endothelial growth factor signaling pathway. Tortuous and disorganized vessel networks formed within a few weeks after the injury and subsequently normalized through vessel regression in a few months. Analyses of the repair process of injured single blood vessels revealed that severed vessels elongated upon injury and anastomosed with each other. Thereafter, repaired vessels and adjacent uninjured vessels became tortuous by increasing the number of ECs. In parallel, PCs divided and migrated to cover the tortuous blood vessels. ECs sprouted from the PC-covered tortuous vessels, suggesting that EC sprouting does not require PC detachment from the vessel wall. Thus, live imaging of cutaneous angiogenesis in adult zebrafish enables us to clarify how ECs and PCs develop new blood vessels during cutaneous angiogenesis.

Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish.

Mural cells (MCs) consisting of vascular smooth muscle cells and pericytes cover the endothelial cells (ECs) to regulate vascular stability and homeostasis. Here, we clarified the mechanism by which MCs develop and cover ECs by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo To cover cranial vessels, MCs derived from either neural crest cells or mesoderm emerged around the preformed EC tubes, proliferated and migrated along EC tubes. During their migration, the MCs moved forward by extending their processes along the inter-EC junctions, suggesting a role for inter-EC junctions as a scaffold for MC migration. In the trunk vasculature, MCs derived from mesoderm covered the ventral side of the dorsal aorta (DA), but not the posterior cardinal vein. Furthermore, the MCs migrating from the DA or emerging around intersegmental vessels (ISVs) preferentially covered arterial ISVs rather than venous ISVs, indicating that MCs mostly cover arteries during vascular development. Thus, live imaging and lineage tracing enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs.

Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling.

RATIONALE: Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. OBJECTIVE: Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9ß1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development. METHODS AND RESULTS: We generated Polydom-deficient mice. Polydom-/- mice showed severe edema and died immediately after birth because of respiratory failure. We found that although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom-/- embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2 (forkhead box protein c2), a transcription factor involved in lymphatic remodeling, was decreased in Polydom-/- mice. Polydom bound to the lymphangiogenic factor Ang-2 (angiopoietin-2), which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for angiopoietins were also decreased in Polydom-/- mice. CONCLUSIONS: Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system.

An Evolutionarily Conserved Role for Polydom/Svep1 During Lymphatic Vessel Formation.

RATIONALE: Lymphatic vessel formation and function constitutes a physiologically and pathophysiologically important process, but its genetic control is not well understood. OBJECTIVE: Here, we identify the secreted Polydom/Svep1 protein as essential for the formation of the lymphatic vasculature. We analyzed mutants in mice and zebrafish to gain insight into the role of Polydom/Svep1 in the lymphangiogenic process. METHODS AND RESULTS: Phenotypic analysis of zebrafish polydom/svep1 mutants showed a decrease in venous and lymphovenous sprouting, which leads to an increased number of intersegmental arteries. A reduced number of primordial lymphatic cells populated the horizontal myoseptum region but failed to migrate dorsally or ventrally, resulting in severe reduction of the lymphatic trunk vasculature. Corresponding mutants in the mouse Polydom/Svep1 gene showed normal egression of Prox-1+ cells from the cardinal vein at E10.5, but at E12.5, the tight association between the cardinal vein and lymphatic endothelial cells at the first lymphovenous contact site was abnormal. Furthermore, mesenteric lymphatic structures at E18.5 failed to undergo remodeling events in mutants and lacked lymphatic valves. In both fish and mouse embryos, the expression of the gene suggests a nonendothelial and noncell autonomous mechanism. CONCLUSIONS: Our data identify zebrafish and mouse Polydom/Svep1 as essential extracellular factors for lymphangiogenesis. Expression of the respective genes by mesenchymal cells in intimate proximity with venous and lymphatic endothelial cells is required for sprouting and migratory events in zebrafish and for remodeling events of the lymphatic intraluminal valves in mouse embryos.

Cardiomyokines from the heart.

The heart is regarded as an endocrine organ as well as a pump for circulation, since atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were discovered in cardiomyocytes to be secreted as hormones. Both ANP and BNP bind to their receptors expressed on remote organs, such as kidneys and blood vessels; therefore, the heart controls the circulation by pumping blood and by secreting endocrine peptides. Cardiomyocytes secrete other peptides besides natriuretic peptides. Although most of such cardiomyocyte-derived peptides act on the heart in autocrine/paracrine fashions, several peptides target remote organs. In this review, to overview current knowledge of endocrine properties of the heart, we focus on cardiomyocyte-derived peptides (cardiomyokines) that act on the remote organs as well as the heart. Cardiomyokines act on remote organs to regulate cardiovascular homeostasis, systemic metabolism, and inflammation. Therefore, through its endocrine function, the heart can maintain physiological conditions and prevent organ damage under pathological conditions.