Variations in Surgical Procedures for Hind Limb Ischaemia Mouse Models Result in differences in Collateral Formation

Hellingman, A.A.; Bastiaansen, A.J.N.M.; Vries, Margreet R. de; Seghers, Leonard; Lijkwan, Maarten A.; Löwik, Clemens W.G.M.; Hamming, Jaap F.; Quax, Paul H.A.

doi:10.1016/j.ejvs.2010.07.009

Cited by 87 publications

(112 citation statements)

References 28 publications

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“…Additionally, previous studies have shown that the therapeutic window ranges from 1 to 3 weeks, with complete blood flow recovery in untreated control animals after these time points (Hellingman et al, 2010). Therefore, we used a single administration to analyze the effect on neovascularization.…”

Section: Discussionmentioning

confidence: 99%

“…Double electrocoagulation of both the common femoral artery and the popliteal artery distally was performed because it could provide a larger therapeutic window (Hellingman et al, 2010). This enables a better analysis of the enhancing effects of MC-shPHD2 on arteriogenesis.…”

Section: Surgical Procedures To Induce Hindlimb Ischemiamentioning

confidence: 99%

“…C57Bl6 mice possess a well-known fast recovery after hindlimb ischemia induction (Hellingman et al, 2010). Mice 42 LIJKWAN ET AL.…”

Section: Surgical Procedures To Induce Hindlimb Ischemiamentioning

confidence: 99%

“…A skin incision was made unilaterally from the left inguinal region to the knee. For a double-coagulation model such as that used in this study, both the common femoral artery and the popliteal artery were dissected from the nerve and vein as described before (Hellingman et al, 2010). An electrocoagulation of the common femoral artery was performed and followed by an electrocoagulation of the popliteal artery.…”

Section: Surgical Procedures To Induce Hindlimb Ischemiamentioning

confidence: 99%

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Short Hairpin RNA Gene Silencing of Prolyl Hydroxylase-2 with a Minicircle Vector Improves Neovascularization of Hindlimb Ischemia

LijkwanMaarten

HellingmanAlwine²,

BosErnst³

et al. 2014

Human Gene Therapy

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In this study, we target the hypoxia inducible factor-1 alpha (HIF-1-alpha) pathway by short hairpin RNA interference therapy targeting prolyl hydroxylase-2 (shPHD2). We use the minicircle (MC) vector technology as an alternative for conventional nonviral plasmid (PL) vectors in order to improve neovascularization after unilateral hindlimb ischemia in a murine model. Gene expression and transfection efficiency of MC and PL, both in vitro and in vivo, were assessed using bioluminescence imaging (BLI) and firefly luciferase (Luc) reporter gene. C57Bl6 mice underwent unilateral electrocoagulation of the femoral artery and gastrocnemic muscle injection with MC-shPHD2, PL-shPHD2, or phosphate-buffered saline (PBS) as control. Blood flow recovery was monitored using laser Doppler perfusion imaging, and collaterals were visualized by immunohistochemistry and angiography. MC-Luc showed a 4.6-fold higher in vitro BLI signal compared with PL-Luc. BLI signals in vivo were 4.3 · 10 5 -3.3 · 10 5 (MC-Luc) versus 0.4 · 10 5 -0.3 · 10 5 (PL-Luc) at day 28 ( p = 0.016). Compared with PL-shPHD2 or PBS, MC-shPHD2 significantly improved blood flow recovery, up to 50% from day 3 until day 14 after ischemia induction. MC-shPHD2 significantly increased collateral density and capillary density, as monitored by alpha-smooth muscle actin expression and CD31 + expression, respectively. Angiography data confirmed the histological findings. Significant downregulation of PHD2 mRNA levels by MCshPHD2 was confirmed by quantitative polymerase chain reaction. Finally, Western blot analysis confirmed significantly higher levels of HIF-1-alpha protein by MC-shPHD2, compared with PL-shPHD2 and PBS. This study provides initial evidence of a new potential therapeutic approach for peripheral artery disease. The combination of HIF-1-alpha pathway targeting by shPHD2 with the robust nonviral MC plasmid improved postischemic neovascularization, making this approach a promising potential treatment option for critical limb ischemia.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Surgical Procedures To Induce Hindlimb Ischemiamentioning

confidence: 99%

“…C57Bl6 mice possess a well-known fast recovery after hindlimb ischemia induction (Hellingman et al, 2010). Mice 42 LIJKWAN ET AL.…”

Section: Surgical Procedures To Induce Hindlimb Ischemiamentioning

confidence: 99%

Section: Surgical Procedures To Induce Hindlimb Ischemiamentioning

confidence: 99%

See 2 more Smart Citations

Short Hairpin RNA Gene Silencing of Prolyl Hydroxylase-2 with a Minicircle Vector Improves Neovascularization of Hindlimb Ischemia

LijkwanMaarten

HellingmanAlwine²,

BosErnst³

et al. 2014

Human Gene Therapy

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show abstract

“…Hind limb ischemia was induced as described before (Hellingman et al, 2010;Bastiaansen et al, 2013). Briefly, animals were sedated with an intraperitoneal injection of 5 mg/kg Dormicum, 0.5 mg/kg Domitor, and 0.05 mg/kg Fentanyl.…”

Section: Animal Modelmentioning

confidence: 99%

CXCL1 microspheres: a novel tool to stimulate arteriogenesis

Caolo

Vries

Zupancich³

et al. 2015

Drug Delivery

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Context: After arterial occlusion, diametrical growth of pre-existing natural bypasses around the obstruction, i.e. arteriogenesis, is the body's main coping mechanism. We have shown before that continuous infusion of chemokine (C-X-C motif) ligand 1 (CXCL1) promotes arteriogenesis in a rodent hind limb ischemia model. Objective: For clinical translation of these positive results, we developed a new administration strategy of local and sustained delivery. Here, we investigate the therapeutic potential of CXCL1 in a drug delivery system based on microspheres. Materials and methods: We generated poly(ester amide) (PEA) microspheres loaded with CXCL1 and evaluated them in vitro for cellular toxicity and chemokine release characteristics. In vivo, murine femoral arteries were ligated and CXCL1 was administered either intra-arterially via osmopump or intramuscularly encapsulated in biodegradable microspheres. Perfusion recovery was measured with Laser-Doppler. Results: The developed microspheres were not cytotoxic and displayed a sustained chemokine release up to 28 d in vitro. The amount of released CXCL1 was 100-fold higher than levels in native ligated hind limb. Also, the CXCL1-loaded microspheres significantly enhanced perfusion recovery at day 7 after ligation compared with both saline and non-loaded conditions (55.4 ± 5.0% CXCL1-loaded microspheres versus 43.1 ± 4.5% non-loaded microspheres; n ¼ 8-9; p50.05). On day 21 after ligation, the CXCL1-loaded microspheres performed even better than continuous CXCL1 administration (102.1 ± 4.4% CXCL1-loaded microspheres versus 85.7 ± 4.8% CXCL1 osmopump; n ¼ 9; p50.05). Conclusion: Our results demonstrate a proof of concept that sustained, local delivery of CXCL1 encapsulated in PEA microspheres provides a new tool to stimulate arteriogenesis in vivo.

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Pre‐cultured, cell‐encapsulating fibrin microbeads for the vascularization of ischemic tissues

Friend,

Beamish,

Margolis

et al. 2023

J Biomedical Materials Res

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There is a significant clinical need to develop effective vascularization strategies for tissue engineering and the treatment of ischemic pathologies. In patients afflicted with critical limb ischemia, comorbidities may limit common revascularization strategies. Cell‐encapsulating modular microbeads possess a variety of advantageous properties, including the ability to support prevascularization in vitro while retaining the ability to be injected in a minimally invasive manner in vivo. Here, fibrin microbeads containing human umbilical vein endothelial cells (HUVEC) and bone marrow‐derived mesenchymal stromal cells (MSC) were cultured in suspension for 3 days (D3 PC microbeads) before being implanted within intramuscular pockets in a SCID mouse model of hindlimb ischemia. By 14 days post‐surgery, animals treated with D3 PC microbeads showed increased macroscopic reperfusion of ischemic foot pads and improved limb salvage compared to the cellular controls. Delivery of HUVEC and MSC via microbeads led to the formation of extensive microvascular networks throughout the implants. Engineered vessels of human origins showed evidence of inosculation with host vasculature, as indicated by erythrocytes present in hCD31+ vessels. Over time, the total number of human‐derived vessels within the implant region decreased as networks remodeled and an increase in mature, pericyte‐supported vascular structures was observed. Our findings highlight the potential therapeutic benefit of developing modular, prevascularized microbeads as a minimally invasive therapeutic for treating ischemic tissues.

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Variations in Surgical Procedures for Hind Limb Ischaemia Mouse Models Result in differences in Collateral Formation

Cited by 87 publications

References 28 publications

Short Hairpin RNA Gene Silencing of Prolyl Hydroxylase-2 with a Minicircle Vector Improves Neovascularization of Hindlimb Ischemia

Short Hairpin RNA Gene Silencing of Prolyl Hydroxylase-2 with a Minicircle Vector Improves Neovascularization of Hindlimb Ischemia

CXCL1 microspheres: a novel tool to stimulate arteriogenesis

Pre‐cultured, cell‐encapsulating fibrin microbeads for the vascularization of ischemic tissues

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