Alterations in endothelial cell proliferation and apoptosis contribute to vascular remodeling following hind-limb ischemia in rabbits

Developmental endothelial locus-1 (Del-1) is an endothelial cell-derived secreted protein circulating in blood and associated with the cell surface and the extracellular matrix. As we previously demonstrated, Del-1 restricts leukocyte recruitment by inhibiting the β2-integrin, LFA-1. Leukocytes and progenitor cells (PC) may contribute to angiogenesis. The role of endogenous Del-1 in angiogenesis is elusive. We found, that physiological angiogenesis of the developing retina was not affected in the Del-1-/- mice compared to the wildtype (WT) mice. Surprisingly, Del-1-/- mice displayed a significantly increased angiogenic response compared to WT mice after induction of hind limb ischemia (144 ± 6 % increase of capillary density) and retinal ischemia (retinopathy of prematurity model) suggesting that endogenous Del-1 is an inhibitor of ischemia-induced neovascularization. Silencing of Del-1 with siRNA did not affect the angiogenic sprouting of endothelial cell (EC) spheroids, indicating that Del-1 blocks angiogenesis in a non-endothelial cell autonomous pathway. Soluble Del-1 blocked the adhesion of inflammatory cells on EC monolayers. In line with these results, ischemic muscles and ischemic retinae from Del-1-/- mice displayed an enhanced infiltration with inflammatory cells compared to the WT mice. Since Del-1 blocks inflammatory cell homing by inhibiting the leukocytic LFA-1-integrin, we addressed the role of the Del-1/LFA-1-integrin interaction on the inhibitory function of endogenous Del-1 on angiogenesis. Indeed, Del-1/LFA-1-double deficiency reversed the pro-angiogenic phenotype of the Del-1-/- mice to the level of WT mice in the model of hind limb ischemia. Thus, the inhibitory role of Del-1 on neovascularization is mediated by the interaction of Del-1 with the LFA-1-integrin. Moreover, Del-1-deficiency led to an increased homing of intravenously injected murine fluorescence-labeled WT Lin- BM PC in ischemic muscles in comparison to WT mice after the induction of hind limb ischemia. Taken together, Del-1 acts as a negative regulator of ischemia-induced angiogenesis by interacting with the LFA-1-integrin expressed in hematopoietic cells, thereby inhibiting the homing of hematopoietic cells to ischemic tissues.

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Marked alterations in endothelial proliferation and apoptosis follow the induction of hind-limb ischemia in rabbits

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(02)80912-3 ◽

2002 ◽

Vol 39 ◽

pp. 206

Author(s):

Qunsheng Dai ◽

Doris A. Taylor ◽

Brian H. Annex

Keyword(s):

Hind Limb ◽

Limb Ischemia ◽

Hind Limb Ischemia ◽

Endothelial Proliferation ◽

Proliferation And Apoptosis

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Effects of microRNA-133b on retinal vascular endothelial cell proliferation and apoptosis through angiotensinogen-mediated angiotensin II- extracellular signal-regulated kinase 1/2 signalling pathway in rats with diabetic retinopathy

Acta Ophthalmologica ◽

10.1111/aos.13715 ◽

2018 ◽

Vol 96 (5) ◽

pp. e626-e635 ◽

Cited By ~ 3

Author(s):

Tao-Tao Liu ◽

Qian Hao ◽

Yan Zhang ◽

Zhao-Hui Li ◽

Zhi-Hua Cui ◽

...

Keyword(s):

Cell Proliferation ◽

Diabetic Retinopathy ◽

Endothelial Cell ◽

Vascular Endothelial Cell ◽

Endothelial Cell Proliferation ◽

Vascular Endothelial ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Proliferation And Apoptosis ◽

Retinal Vascular Endothelial Cell

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Hypoxia Does neither Stimulate Pulmonary Artery Endothelial Cell Proliferation in Mice and Rats with Pulmonary Hypertension and Vascular Remodeling nor in Human Pulmonary Artery Endothelial Cells

Journal of Vascular Research ◽

10.1159/000327005 ◽

2011 ◽

Vol 48 (6) ◽

pp. 465-475 ◽

Cited By ~ 21

Author(s):

Lunyin Yu ◽

Charles A. Hales

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Pulmonary Hypertension ◽

Endothelial Cell ◽

Pulmonary Artery ◽

Vascular Remodeling ◽

Endothelial Cell Proliferation ◽

Human Pulmonary Artery ◽

Pulmonary Artery Endothelial Cell

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Thrombospondin-4 (TSP4) gene-modified bone marrow stromal cells (BMSCs) promote the effect of therapeutic angiogenesis in critical limb ischemia (CLI) of diabetic rats

10.21203/rs.2.15779/v1 ◽

2019 ◽

Author(s):

Qian Zhang ◽

Tao Wang ◽

Xiangfeng Wu ◽

Ying Wang ◽

Xuanqin Wu ◽

...

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Motor Function ◽

Limb Ischemia ◽

Tube Formation ◽

Endothelial Cell Proliferation ◽

Thrombospondin 4

Abstract Background: Critical limb ischemia (CLI) is the leading cause of lower limb amputation. Traditional treatments for CLI have limitations. Studies have shown that thrombospondin-4 (TSP4) can promote the growth of neovascularization. Results: In this study, we observed the angiogenesis efficiency of TSP4-overexpressing BMSC transplantation in CLI treatment. The recombinant FT106-tsp4-gfp lentiviral vector plasmid was constructed and transfected into 293FT cells. Primary BMSCs were successfully infected with the tsp4 virus, and TSP4 overexpression was confirmed before TSP4-BMSCs infusion. In vitro, TSP4-BMSCs were co-cultured with human umbilical vein endothelial cells (HUVECs). Vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) secretion were measured in the co-culture supernatants by ELISA. The effect of TSP4-BMSCs on endothelial cell proliferation and migration was detected. Meanwhile, the effects of TSP4-BMSC on the angiogenesis of endothelial cells were tested by tube formation experiment and arterial ring test. In vivo, a rat CLI model was established, and 60 CLI rats were randomly divided into the CLI, BMSC + CLI and TSP4-BMSC + CLI groups. The effect of TSP4-BMSC on angiogenesis was detected by the motor function, immunohistochemistry and immunofluorescence staining assays. Neovascular density was detected by digital substraction angiography (DSA). Our results demonstrated that TSP4-BMSCs obviously increased TSP4, VEGF, Ang-1, MMP9, MMP2 and p-Cdc42/Rac1 expression in endothelial cells. TSP4-BMSCs treatment notably upregulated the TGF-β/smad2/3 signal pathway in HUVECs. In vivo, TSP4-BMSCs improved the motor function score of the CLI rats and increased MMP2, MMP9, Ang-1, VEGF and vWF protein expression in tissue of the ischaemic area. Meanwhile, new blood vessels can be observed around the ischemic area after TSP4-BMSCs treatment. Conclusion: Our data illustrate that TSP4-BMSCs can promote endothelial cell proliferation, migration, tube formation and the recovery of motor function in diabetic hind limb ischaemic rats. TSP4-BMSCs have better therapeutic effects than BMSCs.

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Thrombospondin-4 (TSP4) gene-modified bone marrow stromal cells (BMSCs) promote the effect of therapeutic angiogenesis in critical limb ischemia (CLI) of diabetic rats

10.21203/rs.3.rs-15860/v1 ◽

2020 ◽

Author(s):

Qian Zhang ◽

Tao Wang ◽

Xiangfeng Wu ◽

Ying Wang ◽

Xuanqin Wu ◽

...

Keyword(s):

Cell Proliferation ◽

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Motor Function ◽

Limb Ischemia ◽

Tube Formation ◽

Endothelial Cell Proliferation ◽

Thrombospondin 4

Abstract Background Critical limb ischemia (CLI) is the leading cause of lower limb amputation. Traditional treatments for CLI have limitations. Studies have shown that thrombospondin-4 (TSP4) can promote the growth of neovascularization. In this study, we observed the angiogenesis efficiency of TSP4-overexpressing BMSC transplantation in CLI treatment. Methods The recombinant FT106-tsp4-gfp lentiviral vector plasmid was constructed and transfected into 293FT cells. Primary BMSCs were successfully infected with the tsp4 virus, and TSP4 overexpression was confirmed before TSP4-BMSCs infusion. In vitro, TSP4-BMSCs were co-cultured with human umbilical vein endothelial cells (HUVECs). Vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) secretion were measured in the co-culture supernatants by ELISA. The effect of TSP4-BMSCs on endothelial cell proliferation and migration was detected. Meanwhile, the effects of TSP4-BMSC on the angiogenesis of endothelial cells were tested by tube formation experiment and arterial ring test. In vivo, a rat CLI model was established, and 60 CLI rats were randomly divided into the CLI, BMSC + CLI and TSP4-BMSC + CLI groups. The effect of TSP4-BMSC on angiogenesis was detected by the motor function, immunohistochemistry and immunofluorescence staining assays. Neovascular density was detected by digital substraction angiography (DSA). Results Our results demonstrated that TSP4-BMSCs obviously increased TSP4, VEGF, Ang-1, MMP9, MMP2 and p-Cdc42/Rac1 expression in endothelial cells. TSP4-BMSCs treatment notably upregulated the TGF-β/smad2/3 signal pathway in HUVECs. In vivo, TSP4-BMSCs improved the motor function score of the CLI rats and increased MMP2, MMP9, Ang-1, VEGF and vWF protein expression in tissue of the ischaemic area. Meanwhile, new blood vessels can be observed around the ischemic area after TSP4-BMSCs treatment. Conclusions Our data illustrate that TSP4-BMSCs can promote endothelial cell proliferation, migration, tube formation and the recovery of motor function in diabetic hind limb ischaemic rats. TSP4-BMSCs have better therapeutic effects than BMSCs.

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Hypoxia induces different genes in the lungs of rats compared with mice

Physiological Genomics ◽

10.1152/physiolgenomics.00081.2001 ◽

2003 ◽

Vol 12 (3) ◽

pp. 209-219 ◽

Cited By ~ 56

Author(s):

Yasushi Hoshikawa ◽

Patrick Nana-Sinkam ◽

Mark D. Moore ◽

Sylk Sotto-Santiago ◽

Tzulip Phang ◽

...

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Endothelial Cell ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Gene Expression Pattern ◽

Endothelial Cell Proliferation ◽

Pulmonary Vascular Remodeling ◽

Hypoxic Conditions ◽

Expression Of Genes

Different animal species have a varying response to hypoxia. Mice develop less pulmonary artery thickening after chronic hypoxia exposure than rats. We hypothesized that the lung tissue gene expression pattern displayed in hypoxic rats would differ from that of hypoxic mice. We exposed Sprague-Dawley rats and C57BL/6 mice to both 1 and 3 wk of hypobaric hypoxia. Although both species developed pulmonary hypertension, mice showed less pulmonary vascular remodeling than rats. Microarray gene analysis demonstrated a distinct pattern of gene expression between mice and rats when exposed to hypoxic conditions. In addition, some genes appeared to be more responsive at an earlier time point of 1 wk of hypoxia. Hypoxic conditions in the rat induce genes involved in endothelial cell proliferation, repression of apoptosis, and vasodilation. Mice exposed to hypoxic conditions decrease the expression of genes involved in vasodilation and in endothelial cell proliferation. Although we cannot determine whether the differential expression of genes during chronic hypoxia is cause or consequence of the differential pulmonary vascular remodeling, we propose that a balance between over- and under-expression of a selective group of genes may be responsible for lung vascular remodeling and vascular tone control.

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