Bradykinin-pretreated Human cardiac-specific c-kit+ Cells Enhance Exosomal miR-3059-5p and Promote Angiogenesis Against Hindlimb Ischemia in mice

Li, Jingzhou; Song, Fei; Chen, Ruolan; Yang, Jinjuan; Liu, Jie; Huang, Li; Duan, Fuyu; Kou, Meng; Lian, Boon Xuan; Zhou, Xiaoxia; Han, Weimin; Liang, Mao; Wu, Chan; Wu, Wei‐Yin; Wei, Rui; Chen, Hao; Xu, Aimin; Tse, Hung-Fat; Lian, Qizhou; Li, Gang; Wang, Yan

doi:10.1007/s12015-023-10591-5

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…After treatment, the migration ability of the HUVECs was tested by using the Transwell assay as previously reported. 22 , 23 , 24 , 25 Briefly, a total of 2 × 10 4 HUVECs (passage 3–8) were suspended in 200 μL ECM medium (0% FBS) and seeded in a modified Boyden chamber with an 8 μm‐pore polycarbonate membrane (Corning, USA) for 30 min. The lower chambers were placed with 600 μL ECM medium (2.5% FBS).…”

Section: Methodsmentioning

confidence: 99%

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Liu,

Song,

Zhou

et al. 2024

J Cellular Molecular Medi

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Dysregulated angiogenesis leads to neovascularization, which can promote or exacerbate various diseases. Previous studies have proved that NEDD4L plays an important role in hypertension and atherosclerosis. Hence, we hypothesized that NEDD4L may be a critical regulator of endothelial cell (EC) function. This study aimed to define the role of NEDD4L in regulating EC angiogenesis and elucidate their underlying mechanisms. Loss‐ and gain‐of‐function of NEDD4L detected the angiogenesis and mobility role in human umbilical vein endothelial cells (HUVECs) using Matrigel tube formation assay, cell proliferation and migration. Pharmacological pathway inhibitors and western blot were used to determine the underlying mechanism of NEDD4L‐regulated endothelial functions. Knockdown of NEDD4L suppressed tube formation, cell proliferation and cell migration in HUVECs, whereas NEDD4L overexpression promoted these functions. Moreover, NEDD4L‐regulated angiogenesis and cell progression are associated with the phosphorylation of Akt, Erk1/2 and eNOS and the expression of VEGFR2 and cyclin D1 and D3. Mechanically, further evidence was confirmed by using Akt blocker MK‐2206, Erk1/2 blocker U0126 and eNOS blocker L‐NAME. Overexpression NEDD4L‐promoted angiogenesis, cell migration and cell proliferation were restrained by these inhibitors. In addition, overexpression NEDD4L‐promoted cell cycle‐related proteins cyclin D1 and D3 were also suppressed by Akt blocker MK‐2206, Erk1/2 blocker U0126 and eNOS blocker L‐NAME. Our results demonstrated a novel finding that NEDD4L promotes angiogenesis and cell progression by regulating the Akt/Erk/eNOS pathways.

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Section: Methodsmentioning

confidence: 99%

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Liu,

Song,

Zhou

et al. 2024

J Cellular Molecular Medi

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“…Unilateral HLI was induced, as previously reported. 28 Briefly, mice were anesthetised by isoflurane vaporisation. The entire femoral artery was exposed and ligated using nylon thread.…”

Section: Methodsmentioning

confidence: 99%

Deletion of endothelial IGFBP5 protects against ischaemic hindlimb injury by promoting angiogenesis

Song,

Hu,

Hong

et al. 2024

Clinical & Translational Med

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BackgroundAngiogenesis is critical for forming new blood vessels from antedating vascular vessels. The endothelium is essential for angiogenesis, vascular remodelling and minimisation of functional deficits following ischaemia. The insulin‐like growth factor (IGF) family is crucial for angiogenesis. Insulin‐like growth factor‐binding protein 5 (IGFBP5), a binding protein of the IGF family, may have places in angiogenesis, but the mechanisms are not yet completely understood. We sought to probe whether IGFBP5 is involved in pathological angiogenesis and uncover the molecular mechanisms behind it.Methods and resultsIGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R‐mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel‐Lindau (VHL)‐regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post‐HLI.ConclusionOur findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis‐related conditions.

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“…The -Kit signaling pathway has been extensively studied in the cancer field, and its angiogenic properties are well characterized [ 19 , 20 ]. Moreover, a few studies, including one from our group [ 21 ], have shown the beneficial effect of global c-Kit in improving arteriogenesis and limb perfusion during hindlimb ischemia [ 22 , 23 ]. However, the specific effect of vascular c-Kit signaling is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Loss of c-Kit in Endothelial Cells Protects against Hindlimb Ischemia

Falero-Diaz,

Barboza,

Vazquez-Padron

et al. 2024

Biomedicines

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Background: Critical limb ischemia (CLI) is the end stage of peripheral artery disease (PAD), and around 30% of CLI patients are ineligible for current treatments. The angiogenic benefits of c-Kit have been reported in the ischemia scenario; however, the present study demonstrates the effects of specific endothelial c-Kit signaling in arteriogenesis during hindlimb ischemia. Methods: We created conditional knockout mouse models that decrease c-Kit (c-Kit VE-Cadherin CreERT2—c-Kit) or its ligand (SCF VE-Cadherin CreERT2—SCF) specifically in endothelial cells (ECs) after tamoxifen treatment. These mice and a control group (wild-type VE-Cadherin CreERT2—WT) were subjected to hindlimb ischemia or aortic crush to evaluate perfusion/arteriogenesis and endothelial barrier permeability, respectively. Results: Our data confirmed the lower gene expression of c-Kit and SCF in the ECs of c-Kit and SCF mice, respectively. In addition, we confirmed the lower percentage of ECs positive for c-Kit in c-Kit mice. Further, we found that c-Kit and SCF mice had better limb perfusion and arteriogenesis compared to WT mice. We also demonstrated that c-Kit and SCF mice had a preserved endothelial barrier after aortic crush compared to WT. Conclusions: Our data demonstrate the deleterious effects of endothelial SCF/c-Kit signaling on arteriogenesis and endothelial barrier integrity.

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Bradykinin-pretreated Human cardiac-specific c-kit+ Cells Enhance Exosomal miR-3059-5p and Promote Angiogenesis Against Hindlimb Ischemia in mice

Cited by 4 publications

References 47 publications

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

NEDD4L is a promoter for angiogenesis and cell proliferation in human umbilical vein endothelial cells

Deletion of endothelial IGFBP5 protects against ischaemic hindlimb injury by promoting angiogenesis

Loss of c-Kit in Endothelial Cells Protects against Hindlimb Ischemia

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