Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart

Shang, Rui; Lal, Nathaniel; Lee, Chae Syng; Zhai, Yajie; Puri, Karanjit; Seira, Oscar; Boushel, Robert; Sultan, Ibrahim; Räsänen, Markus; Alitalo, Kari; Hussein, Bahira; Rodrigues, Brian

doi:10.1152/ajpendo.00219.2021

Cited by 7 publications

(11 citation statements)

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“…We have previously reported that in response to exogenous insulin, Tg hearts demonstrate increased insulin sensitivity. 19 In this study, when exposed to insulin, WT hearts showed increased phosphorylation of the insulin receptor, an effect that was significantly higher in Tg hearts (Figure S2). Given that the tissue-specific response of LPL to insulin is variable, with a decrease in cardiac LPL activity observed following feeding due to its associated augmentation of insulin, we hypothesized that the reduction in vascular LPL activity in Tg hearts is secondary to the altered insulin action.…”

Section: Fasting and Chemically Induced Insulin Reduction Unmask The ...mentioning

confidence: 55%

“…Surgically extracted hearts from WT and VEGFB Tg fed and fasted rats were placed in an ice-cold preservation solution, and left ventricle tissues were sectioned and permeabilized before the respirometry measurements as described previously. 19 Echocardiography VEGFB Tg and WT rats were assigned for echocardiography using the Vevo2100 Ultrasound System (Fujifilm VisualSonics Inc, Toronto, Ontario, Canada), equipped with a high-frequency ultrasound probe (MS250-0264). Briefly, animals were anesthetized with isoflurane for 10 to 15 minutes (induction, 4.5%; maintenance, 2.0%; Baxter International Inc, Deerfield, IL, United States), and placed on a heated platform to maintain body temperature at 36 °C to 37 °C.…”

Section: Mitochondrial Respirometry Measurementsmentioning

confidence: 99%

“…In this regard, in vitro studies report a direct role of VEGFB in regulating FA metabolism by increasing the expression of FATPs (fatty acid transporter proteins) in EC 18 and mitochondrial respiration in myocytes. 19 Paradoxically, different effects were observed in vivo, as cardiac-specific overexpression of VEGFB with its expanded coronary vasculature and augmented insulin action demonstrated a lowered heparin-releasable LPL activity 19 and FA utilization. 17 Currently, the mechanism behind this in vivo metabolic effect of VEGFB is unclear but could be a secondary effect due to the inhibitory action of insulin.…”

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confidence: 99%

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Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization

Shang,

Lee,

Wang

et al. 2024

ATVB

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BACKGROUND: The heart relies heavily on external fatty acid (FA) for energy production. VEGFB (vascular endothelial growth factor B) has been shown to promote endothelial FA uptake by upregulating FA transporters. However, its impact on LPL (lipoprotein lipase)–mediated lipolysis of lipoproteins, a major source of FA for cardiac use, is unknown. METHODS: VEGFB transgenic (Tg) rats were generated by using the α-myosin heavy chain promoter to drive cardiomyocyte-specific overexpression. To measure coronary LPL activity, Langendorff hearts were perfused with heparin. In vivo positron emission tomography imaging with [ 18 F]-triglyceride-fluoro-6-thia-heptadecanoic acid and [ 11 C]-palmitate was used to determine cardiac FA uptake. Mitochondrial FA oxidation was evaluated by high-resolution respirometry. Streptozotocin was used to induce diabetes, and cardiac function was monitored using echocardiography. RESULTS: In Tg hearts, the vectorial transfer of LPL to the vascular lumen is obstructed, resulting in LPL buildup within cardiomyocytes, an effect likely due to coronary vascular development with its associated augmentation of insulin action. With insulin insufficiency following fasting, VEGFB acted unimpeded to facilitate LPL movement and increase its activity at the coronary lumen. In vivo PET imaging following fasting confirmed that VEGFB induced a greater FA uptake to the heart from circulating lipoproteins as compared with plasma-free FAs. As this was associated with augmented mitochondrial oxidation, lipid accumulation in the heart was prevented. We further examined whether this property of VEGFB on cardiac metabolism could be useful following diabetes and its associated cardiac dysfunction, with attendant loss of metabolic flexibility. In Tg hearts, diabetes inhibited myocyte VEGFB gene expression and protein secretion together with its downstream receptor signaling, effects that could explain its lack of cardioprotection. CONCLUSIONS: Our study highlights the novel role of VEGFB in LPL-derived FA supply and utilization. In diabetes, loss of VEGFB action may contribute toward metabolic inflexibility, lipotoxicity, and development of diabetic cardiomyopathy.

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Section: Fasting and Chemically Induced Insulin Reduction Unmask The ...mentioning

confidence: 55%

Section: Mitochondrial Respirometry Measurementsmentioning

confidence: 99%

mentioning

confidence: 99%

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Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization

Shang,

Lee,

Wang

et al. 2024

ATVB

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“…In 2021, a study by Hu et al ( 20 ) also revealed that the effect of VEGFB on lipid metabolism depended on VEGFR1. In addition, it has been observed that VEGFB gene knockout and VEGFR1 deletion in the db/db mouse model can maintain metabolic homeostasis and restore lipid and glucose metabolism ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1

Luo

et al. 2022

Mol Med Rep

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In recent years, studies have demonstrated that vascular endothelial growth factor B (VEGFB) can affect the metabolism of fatty acids and glucose, and it is expected to become a target for the diagnosis and treatment of metabolic diseases such as obesity and diabetes. At present, the specific mechanism that VEGFB regulates lipid and glucose metabolism balance is not completely understood. The present study used systemic VEGFB gene-knockout mice to investigate the effects of downregulation of the VEGFB gene on lipid metabolism and insulin secretion, and to explore the mechanism of the VEGFB pathway involved in the regulation of glucose and lipid metabolism. The morphological changes in the liver and pancreas of mice after VEGFB gene deletion were observed under a light microscope and a scanning electron microscope, and the effects of VEGFB gene deletion on lipid metabolism and blood glucose balance were detected by a serological technique. The detection indexes included total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol. Simultaneously, fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), fasting insulin and glucagon were measured. Insulin sensitivity was assessed by using the insulin tolerance tests and glucose tolerance tests, and function of β-cell islets was evaluated by using the insulin resistance index (HOMA-IR) and pancreatic β-cell secretion index (HOMA-β). Τhe protein expression changes of vascular endothelial growth factor receptor 1 (VEGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in mouse islets were detected by western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) after the VEGFB gene was knocked down to analyze the mechanism of VEGFB that may be involved in glucose and lipid metabolism. It was observed that after VEGFB was knocked down, mouse hepatocytes exhibited steatosis and increased secretory vesicles in islet cells. The lipid metabolism indexes such as TG, TC and LDL increased significantly; however, the levels of FBS, postprandial blood glucose and HbA1c decreased, whereas the glucose tolerance increased. Serum insulin secretion increased and HOMA-IR decreased since VEGFB was knocked down. Western blotting and RT-qPCR results revealed that the expression levels of VEGFR1 and neuropilin-1 decreased after the VEGFB gene was knocked down, while the expression levels of VEGFA and VEGFR2 increased. The absence of VEGFB may be involved in the regulation of glucose and lipid metabolism in mice by activating the VEGFA/VEGFR2 signaling pathway. VEGFB is expected to become a new target for the treatment of metabolic diseases such as obesity and diabetes. At present, the mechanism of VEGFB involved in regulating lipid metabolism and glucose metabolism is not completely clear. It was identified that downregulating VEGFB improved lipid metabolism and insulin resistance. The role of VEGFB/VEGFR1 pathway and other family members in regulating glucose and lipid me...

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“…VEGF-B is co-expressed with a cluster of nuclear encoded mitochondrial genes involved in the oxidative phosphorylation mechanism [ 32 ]. Binding of VEGF-B to VEGF-R1 and NRP-1 promotes the distribution of fatty acid transport proteins (FATP3 and FATP4) on the endothelial cells to facilitate lipid transport where lipoprotein lipase and low-density lipoprotein receptor are merely anchored [ 25 , 32 , 43 , 53 , 60 ]. VEGF-B reduces endothelial cholesterol content by interfering with low-density lipoprotein receptor recycling [ 60 ].…”

Section: Cardioprotective Role Of Vegf-bmentioning

confidence: 99%

Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision?

Mallick

Ylä‐Herttuala

2022

Cells

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Coronary heart disease (CHD) is the leading cause of death around the world. Based on the roles of vascular endothelial growth factor (VEGF) family members to regulate blood and lymphatic vessels and metabolic functions, several therapeutic approaches have been attempted during the last decade. However proangiogenic therapies based on classical VEGF-A have been disappointing. Therefore, it has become important to focus on other VEGFs such as VEGF-B, which is a novel member of the VEGF family. Recent studies have shown the very promising potential of the VEGF-B to treat CHD and heart failure. The aim of this review article is to present the role of VEGF-B in endothelial biology and as a potential therapeutic agent for CHD and heart failure. In addition, key differences between the VEGF-A and VEGF-B effects on endothelial functions are demonstrated.

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Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart

Cited by 7 publications

References 58 publications

Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization

Reduction in Insulin Uncovers a Novel Effect of VEGFB on Cardiac Substrate Utilization

Reducing VEGFB expression regulates the balance of glucose and lipid metabolism in mice via VEGFR1

Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision?

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