Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling

Kivelä, Riikka; Hemanthakumar, Karthik Amudhala; Vaparanta, Katri; Robciuc, Marius R.; Izumiya, Yasuhiro; Kidoya, Hiroyasu; Takakura, Nobuyuki; Peng, Xiao; Sawyer, Douglas B.; Elenius, Klaus; Walsh, Kenneth; Alitalo, Kari

doi:10.1161/circulationaha.118.036099

Cited by 124 publications

(119 citation statements)

References 49 publications

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“…Future work is required to determine the molecular and cellular mechanisms underlying the catch-up and facilitation, which were well correlated with IL-35 promotion of macrophage survival and improvement of wound healing after myocardial infarction ( 85 ). In addition, differences between the IL-35 roles in angiogenesis in HLI and myocardial infarction may also result from potential functions of cardiokines ( 86 ) and myokines ( 87 ).…”

Section: Discussionmentioning

confidence: 99%

“…Of note, the stronger protection of IL-35 in the cardiac muscle than in the skeletal muscle may be due to tissue specificity. In addition, differences between the IL-35 roles in angiogenesis in HLI and myocardial infarction may also result from potential functions of cardiokines ( 86 ) and myokines ( 87 ). These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at the early phase but sparing regenerative angiogenesis at the late phase, which is similar to our recent report that IL-35 inhibits human aortic endothelial cell activation triggered by proatherogenic lipids but spare trained immunity pathway ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

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Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Sun

Shao

et al. 2020

Front. Immunol.

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Interleukin (IL) 35 is a novel immunosuppressive heterodimeric cytokine in IL-12 family. Whether and how IL-35 regulates ischemia-induced angiogenesis in peripheral artery diseases are unrevealed. To fill this important knowledge gap, we used loss-of-function, gain-of-function, omics data analysis, RNA-Seq, in vivo and in vitro experiments, and we have made the following significant findings: i ) IL-35 and its receptor subunit IL-12RB2, but not IL-6ST, are induced in the muscle after hindlimb ischemia (HLI); ii ) HLI-induced angiogenesis is improved in Il12rb2−/− mice, in ApoE−/−/Il12rb2−/− mice compared to WT and ApoE−/− controls, respectively, where hyperlipidemia inhibits angiogenesis in vivo and in vitro; iii ) IL-35 cytokine injection as a gain-of-function approach delays blood perfusion recovery at day 14 after HLI; iv ) IL-35 spares regenerative angiogenesis at the late phase of HLI recovery after day 14 of HLI; v ) Transcriptome analysis of endothelial cells (ECs) at 14 days post-HLI reveals a disturbed extracellular matrix re-organization in IL-35-injected mice; vi ) IL-35 downregulates three reactive oxygen species (ROS) promoters and upregulates one ROS attenuator, which may functionally mediate IL-35 upregulation of anti-angiogenic extracellular matrix proteins in ECs; and vii ) IL-35 inhibits human microvascular EC migration and tube formation in vitro mainly through upregulating anti-angiogenic extracellular matrix-remodeling proteins. These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at early phase but sparing regenerative angiogenesis at late phase.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Sun

Shao

et al. 2020

Front. Immunol.

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“…However, in a subsequent analysis these phenotypes were not confirmed (54). Cardiomyocyte-specific transgenic overexpression of full-length VEGF-B induced expansion of the coronary vasculature, enlargement of myocardial capillaries, mild cardiomyocyte hypertrophy, and promoted in vivo ischemia protection (13,36,37,55). Importantly, the vascular effects did not include vascular leakage, unlike with VEGF overexpression.…”

Section: Vascular Endothelial Growth Factor-bmentioning

confidence: 92%

“…With VEGF and VEGF-C, the titration has proven to be very difficult, and even with low dose local administration, the new vessels are leaky and immature, and the mice often have to be killed (42). In contrast, overexpression of VEGF-B, PlGF or VEGF-D result in modest increase in the vasculature in many tissues, and there is no massive angiogenesis or leakage but rather an enlargement of the existing vessels (13,37,42,43). Interestingly, both VEGF and VEGF-C are essential during development (44,45,46), while the knockout mice for VEGF-B, PlGF and VEGF-D are healthy and viable (47,48,49,50).…”

Section: Angiogenesis-mediated Cardiac Hypertrophymentioning

confidence: 99%

“…The EC-derived signaling via the release of paracrine/ juxtacrine-acting growth factors, termed as angiocrines (6), is now appreciated to be highly organ specific. Angiocrine signaling has been shown to be essential for physiological growth and homeostasis as well as regeneration in several tissues, such as liver, lungs, bone and the heart (6,7,8,9,10,11,12,13). Angiocrines have an important role also in pathological conditions for example, in inflammation and cancer (14), and thus could provide novel targets to treat several diseases.…”

Section: Introductionmentioning

confidence: 99%

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Angiogenesis and angiocrines regulating heart growth

Hemanthakumar

Kivelä

2020

Vascular Biology

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Endothelial cells (ECs) line the inner surface of all blood and lymphatic vessels throughout the body, making endothelium one of the largest tissues. In addition to its transport function, endothelium is now appreciated as a dynamic organ actively participating in angiogenesis and permeability and vascular tone regulation, as well as in the development and regeneration of tissues. The identification of endothelial-derived secreted factors, angiocrines, has revealed non-angiogenic mechanisms of endothelial cells in both physiological and pathological tissue remodeling. In the heart, ECs play a variety of important roles during cardiac development as well as in growth, homeostasis and regeneration of the adult heart. To date, several angiocrines affecting cardiomyocyte growth in response to physiological or pathological stimuli have been identified. In this review, we discuss the effects of angiogenesis and EC-mediated signaling in the regulation of cardiac hypertrophy. Identification of the molecular and metabolic signals from ECs during physiological and pathological cardiac growth could provide novel therapeutic targets to treat heart failure, as endothelium is emerging as one of the potential target organs in cardiovascular and metabolic diseases.

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Generation and Culture of Cardiac Microtissues in a Microfluidic Chip with a Reversible Open Top Enables Electrical Pacing, Dynamic Drug Dosing and Endothelial Cell Co‐Culture

Vivas

IJspeert

Pan

et al. 2022

Adv Materials Technologies

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Cardiovascular disease morbidity has increased worldwide. Organs‐on‐chips and human pluripotent stem cell (hPSC) technologies aid to overcome some of the limitations in cardiac in vitro models. Here, a bi‐compartmental, monolithic heart‐on‐chip device that facilitates porous membrane integration in a single fabrication step is presented. Moreover, the device includes open‐top compartments that allow facile co‐culture of hPSC‐derived cardiomyocytes and human adult cardiac fibroblast into geometrically defined cardiac microtissues. The device can be reversibly closed with a glass seal or a lid with fully customized 3D‐printed pyrolytic carbon electrodes allowing electrical stimulation of cardiac microtissues. A subjacent microfluidic channel allowed localized and dynamic drug administration to the cardiac microtissues, as demonstrated by a chronotropic response to isoprenaline. Moreover, the microfluidic channel can also be populated with human induced pluripotent stem‐derived endothelial cells allowing co‐culture of heterotypic cardiac cells in one device. Overall, this study demonstrates a novel heart‐on‐chip model that systematically integrates an open‐top device with a 3D printed carbon electrode for electrical pacing and culture of cardiac tissues while enabling active perfusion and dynamic drug dosing. Advances in the engineering of human heart‐on‐chip models represent an important step towards making organ‐on‐a‐chip technology a routine aspect of preclinical cardiac drug development.

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Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling

Abstract: Supplemental Digital Content is available in the text.

Cited by 124 publications

References 49 publications

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Angiogenesis and angiocrines regulating heart growth

Generation and Culture of Cardiac Microtissues in a Microfluidic Chip with a Reversible Open Top Enables Electrical Pacing, Dynamic Drug Dosing and Endothelial Cell Co‐Culture

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