Abstract 17597: Endogenous Del-1 is a Negative Regulator of Ischemia-induced Angiogenesis by Interacting With the Leukocytic LFA-1 Integrin

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sebastian Cremer ◽  
Anne Klotzsche-von Ameln ◽  
Alessia Orlandi ◽  
Irina Korovina ◽  
Bettina Gercken ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Hind Limb ◽  
Hematopoietic Cells ◽  
Limb Ischemia ◽  
Inflammatory Cells ◽  
Capillary Density ◽  
Negative Regulator ◽  
Hind Limb Ischemia ◽  
Autonomous Pathway

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.

Abstract 3915: Del-1, A New β2-Integrin Ligand, Which Inhibits Adhesion and Homing of Progenitor Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Emmanouil Chavakis ◽  
Andreas Hain ◽  
Alessia Orlandi ◽  
Guillaume Carmona ◽  
Thomas Quertermous ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Inflammatory Cells ◽  
Inhibitory Effect ◽  
Hind Limb Ischemia ◽  
Beta2 Integrins ◽  
Integrin Ligand

Progenitor cells (PC) are recruited to ischemic tissues and improve neovascularization. Beta2-integrins are essential for adhesion, transmigration and homing of PC to ischemic tissues. Developmental Endothelial Locus-1 (Del-1) is an extracellular matrix protein, that binds alphaVbeta3- and alphaVbeta5-integrins and is up-regulated during ischemia. Therefore, we investigated the role of endogenous Del-1 for angiogenesis and homing functions of PC. The Del-1-deficient mice (Del-1 −/− ) displayed a significantly increased angiogenic response in ischemic muscles in comparison to the wild type (WT) mice in the model of hind limb ischemia. However, when we assessed the role of Del-1 in HUVEC in vitro , silencing of Del-1 by siRNA did not affect angiogenic sprouting. Moreover, the ischemic muscles of Del-1 −/− mice displayed a higher infiltration with CD45 + hematopoietic cells than WT mice, suggesting that Del-1 may have an inhibitory effect on homing of PC and inflammatory cells to ischemic tissues. Interestingly, in adhesion assays human endothelial progenitor cells (EPC) and murine Lin − progenitor cells bound to Del-1 via beta2-integrins, but not via the alphaVbeta3- and alphaVbeta5- integrins. Furthermore, soluble Del-1 significantly inhibited the adhesion of EPC to HUVEC monolayers and to the major beta2-integrin-ligand, ICAM-1, raising the possibility that Del-1 is a beta2-integrin-inhibitor. Indeed, WT murine bone marrow mononuclear cells displayed higher adhesion rates on Del-1-deficient murine lung endothelial cells (LEC) than on WT LEC. In order to investigate the role of Del-1 for in vivo homing of PC, we intravenously injected murine fluorescence-labeled WT Lin − bone marrow PC in WT and Del-1 −/− mice 2 days after the induction of hind limb ischemia. Interestingly, the homing of injected Lin − cells to ischemic muscles was significantly increased in Del-1 −/− in comparison to WT mice (200± 30 % increase). Taken together, endogenous Del-1 is a new beta2-integrin ligand, which blocks beta2-integrin-dependent adhesion and homing of PC to ischemic tissues. It is conceivable, that endogenous Del-1 may reduce ischemia-induced neovascularization through an inhibitory effect on the beta2-integrins of progenitor and inflammatory cells.

Abstract 272: Impaired Arteriogenesis in Cystathionine Gamma-Lyase (CSE) and Endothelial Nitric Oxide Synthase (eNOS) Mutant Mice

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Alvaro F Manrique ◽  
Shyamal C Bir ◽  
Elvis Peter ◽  
Rui Wang ◽  
Christopher G Kevil
Keyword(s):  
Nitric Oxide ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Tissue Perfusion ◽  
Vessel Density ◽  
Mutant Mice ◽  
Arterial Remodeling ◽  
Hind Limb Ischemia ◽  
Over Time

Introduction: Arteriogenesis is an important process involving remodeling of collateral vasculature during chronic or intermittent tissue ischemia. CSE and eNOS are the two principle enzymes for hydrogen sulfide (H 2 S) and Nitric Oxide (NO) generation. Although role of NO during arteriogenesis is partially known, the role of CSE dependent H 2 S production during arteriogenesis remains unknown. Hypothesis/objective: We sought to determine the role of CSE generated H 2 S on arteriogenesis activity of CSE knockout (CSEKO) mice compared to eNOS knock out (eNOSKO) and wild type (WT) mice during hind limb ischemia. Method: Permanent unilateral hind limb ischemia was induced in 12-week-old CSE KO, eNOS KO, and WT mice and studied until day 21. Tissue perfusion was measured using indicator dye blush rates with the SPY Imager system over time along with laser doppler flowmetry. Temporal development of arterial remodeling was also observed using SPY imaging, and vessel number, length and branch morphometry determined over time. Microfil vascular casting was performed to further examine the number of collaterals in ischemic muscles at the end of the study. Histological arteriogenesis was evaluated by vascular smooth muscle actin (SMA) positive vessel density with dual fluorescence staining of anti-CD31 (endothelial positive cell) and anti-α-SMA antibodies. Results: Tissue perfusion was significantly impaired in CSE KO and eNOS KO mice compared to WT mice at different time points throughout the study period. Both CSE KO and eNOS KO mice showed significantly less blush rate than WT mice. SMA positive vessel density was also significantly less in CSE KO and eNOS KO mice than that in WT mice. Conclusion: CSE generated H 2 S and eNOS derived NO play important roles in regulating ischemic arterial remodeling as demonstrated in our studies. The mechanism of impaired arteriogenesis in both mutant mice and the interaction between these two gasotransmitters has yet to be elucidated.

Anti‐Angiogenic Role of Glutaredoxin‐1 in Hind Limb Ischemia

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Yosuke Watanabe ◽  
Colin Murdoch ◽  
Richard Cohen ◽  
Reiko Matsui
Keyword(s):  
Hind Limb ◽  
Limb Ischemia ◽  
Hind Limb Ischemia

scholarly journals The Role of Osteopontin in Recovery from Hind Limb Ischemia

2008 ◽  
Vol 28 (2) ◽  
pp. 290-295 ◽  
Author(s):  
Craig L. Duvall ◽  
Daiana Weiss ◽  
Scott T. Robinson ◽  
Fadi M.F. Alameddine ◽  
Robert E. Guldberg ◽  
...  
Keyword(s):  
Hind Limb ◽  
Limb Ischemia ◽  
Hind Limb Ischemia

scholarly journals Role of Scutellarin in Ameliorating Lung Injury in a Rat Model of Bilateral Hind Limb Ischemia–Reperfusion

2019 ◽  
Vol 302 (11) ◽  
pp. 2070-2081 ◽  
Author(s):  
Marwa A. A. Ibrahim ◽  
Walaa M. Elwan ◽  
Hanan A. Elgendy
Keyword(s):  
Lung Injury ◽  
Rat Model ◽  
Hind Limb ◽  
Ischemia Reperfusion ◽  
Limb Ischemia ◽  
Hind Limb Ischemia

scholarly journals Co-injection of mesenchymal stem cells with endothelial progenitor cells accelerates muscle recovery in hind limb ischemia through an endoglin-dependent mechanism

2017 ◽  
Vol 117 (10) ◽  
pp. 1908-1918 ◽  
Author(s):  
Elisa Rossi ◽  
Céline Goyard ◽  
Audrey Cras ◽  
Blandine Dizier ◽  
Nour Bacha ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Progenitor Cells ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Capillary Density ◽  
Vessel Density ◽  
Muscle Recovery ◽  
Hind Limb Ischemia ◽  
Alu Sequence

SummaryEndothelial colony-forming cells (ECFCs) are progenitor cells committed to endothelial lineages and have robust vasculogenic properties. Mesenchymal stem cells (MSCs) have been described to support ECFC-mediated angiogenic processes in various matrices. However, MSC-ECFC interactions in hind limb ischemia (HLI) are largely unknown. Here we examined whether co-administration of ECFCs and MSCs bolsters vasculogenic activity in nude mice with HLI. In addition, as we have previously shown that endoglin is a key adhesion molecule, we evaluated its involvement in ECFC/MSC interaction. Foot perfusion increased on day 7 after ECFC injection and was even better at 14 days. Co-administration of MSCs significantly increased vessel density and foot perfusion on day 7 but the differences were no longer significant at day 14. Analysis of mouse and human CD31, and in situ hybridization of the human ALU sequence, showed enhanced capillary density in ECFC+MSC mice. When ECFCs were silenced for endoglin, coinjection with MSCs led to lower vessel density and foot perfusion at both 7 and 14 days (p<0.001). Endoglin silencing in ECFCs did not affect MSC differentiation into perivascular cells or other mesenchymal lineages. Endoglin silencing markedly inhibited ECFC adhesion to MSCs. Thus, MSCs, when combined with ECFCs, accelerate muscle recovery in a mouse model of hind limb ischemia, through an endoglindependent mechanism.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals ROLE OF DIALLYL TRISULFIDE IN MURINE PERMANENT HIND LIMB ISCHEMIA

2011 ◽  
Vol 57 (14) ◽  
pp. E1516
Author(s):  
Jagan Beedupalli ◽  
Shyamal C. Bir ◽  
Christopher B. Pattillo ◽  
Christopher G. Kevil
Keyword(s):  
Hind Limb ◽  
Limb Ischemia ◽  
Diallyl Trisulfide ◽  
Hind Limb Ischemia
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