scholarly journals Protease nexin-1 deficiency increases mouse hindlimb neovascularisation following ischemia and accelerates femoral artery perfusion

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonia Selbonne ◽  
Celina Madjene ◽  
Benjamin Salmon ◽  
Yacine Boulaftali ◽  
Marie-Christine Bouton ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Capillary Density ◽  
Leukocyte Recruitment ◽  
Lower Limbs ◽  
Artery Ligation ◽  
Angiogenic Balance ◽  
Important Player ◽  
Protease Nexin ◽  
Artery Perfusion

AbstractWe previously identified the inhibitory serpin protease nexin-1 (PN-1) as an important player of the angiogenic balance with anti-angiogenic activity in physiological conditions. In the present study, we aimed to determine the role of PN-1 on pathological angiogenesis and particularly in response to ischemia, in the mouse model induced by femoral artery ligation. In wild-type (WT) muscle, we observed an upregulation of PN-1 mRNA and protein after ischemia. Angiography analysis showed that femoral artery perfusion was more rapidly restored in PN-1−/− mice than in WT mice. Moreover, immunohistochemistry showed that capillary density increased following ischemia to a greater extent in PN-1−/− than in WT muscles. Moreover, leukocyte recruitment and IL-6 and MCP-1 levels were also increased in PN-1−/− mice compared to WT after ischemia. This increase was accompanied by a higher overexpression of the growth factor midkine, known to promote leukocyte trafficking and to modulate expression of proinflammatory cytokines. Our results thus suggest that the higher expression of midkine observed in PN-1- deficient mice can increase leukocyte recruitment in response to higher levels of MCP-1, finally driving neoangiogenesis. Thus, PN-1 can limit neovascularisation in pathological conditions, including post-ischemic reperfusion of the lower limbs.

Vascular ligation response is independent of p107: stressing the role of the related p130

2003 ◽  
Vol 285 (2) ◽  
pp. H915-H918 ◽  
Author(s):  
Jürgen R. Sindermann ◽  
Christiane Köbbert ◽  
Florian Bauer ◽  
Adriane Skaletz-Rorowski ◽  
Helge Hohage ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Vascular Injury ◽  
Femoral Artery ◽  
Arterial Injury ◽  
Injury Response ◽  
Artery Ligation ◽  
Wall Area ◽  
Carotid Artery Ligation ◽  
Electric Injury

Recent studies have revealed the role of the pRb family members pRb and p130 in the response to vascular injury. We evaluated the arterial injury response in the absence of p107, a protein that shares a high degree of homology with the injury-controlling p130. Carotid artery ligation and perivascular electric injury of the femoral artery were applied to p107 knockout (p107 –/–) mice, and morphometric analysis was performed 3 wk after ligation and electric injury. Arterial vessels of p107 –/– mice were indistinguishable from controls under basal conditions. After carotid artery ligation the p107 –/– mice ( n = 7) did not display an enhanced ligation response compared with controls ( n = 9), which was studied over a distance of ∼450 μm proximal and ∼200 μm distal from the ligation site, with regard to vessel wall area, neointima area, and lumen area. Corresponding with this, morphometric data obtained from the perivascular electric injury of the femoral artery confirmed the lack of enhanced ligation and injury response in the absence of p107. We conclude that the pRb family member p107 is not a key regulator in vascular injury response. These data, in conjunction with previously reported results, indicate that the control of vascular injury response is not a redundant feature of pRb proteins but primarily specific for p130. Further studies on functional domains of p130 and p107 will help to resolve the pathways in vascular injury response.

scholarly journals Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47phox

2015 ◽  
Vol 309 (7) ◽  
pp. H1207-H1217 ◽  
Author(s):  
Matthew R. DiStasi ◽  
Julie A. Mund ◽  
H. Glenn Bohlen ◽  
Steven J. Miller ◽  
David A. Ingram ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Arterial Occlusion ◽  
Whole Body ◽  
Preclinical Model ◽  
Flow Cytometry Analysis ◽  
Artery Ligation ◽  
Multiparametric Flow Cytometry ◽  
Collateral Arteries ◽  
Collateral Growth

The present study was undertaken to establish the role of NADPH oxidase (Nox) in impaired vascular compensation to arterial occlusion that occurs in the presence of risk factors associated with oxidative stress. Diet-induced obese (DIO) mice characterized by multiple comorbidities including diabetes and hyperlipidemia were used as a preclinical model. Arterial occlusion was induced by distal femoral artery ligation in lean and DIO mice. Proximal collateral arteries were identified as the site of major (∼70%) vascular resistance to calf perfusion by distal arterial pressures, which decreased from ∼80 to ∼30 mmHg with ligation in both lean and DIO mice. Two weeks after ligation, significant vascular compensation occurred in lean but not DIO mice as evidenced by increased perfusion (147 ± 48% vs. 49 ± 29%) and collateral diameter (151 ± 30% vs. 44 ± 17%). Vascular mRNA expression of p22phox, Nox2, Nox4, and p47phox were all increased in DIO mice. Treatment of DIO mice with either apocynin or Nox2ds-tat or with whole body ablation of either Nox2 or p47phox ameliorated the impairment in both collateral growth and hindlimb perfusion. Multiparametric flow cytometry analysis demonstrated elevated levels of circulating monocytes in DIO mice without impaired mobilization and demargination after femoral artery ligation. These results establish collateral resistance as the major limitation to calf perfusion in this preclinical model, demonstrate than monocyte mobilization and demarginatin is not suppressed, implicate Nox2-p47phox interactions in the impairment of vascular compensation to arterial occlusion in DIO mice, and suggest that selective Nox component suppression/inhibition may be effective as either primary or adjuvant therapy for claudicants.

scholarly journals A modified axillo-femoral perfusion for acute type a aortic dissection accompanied with lower limb malperfusion

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Qianzhen Li ◽  
Liangwan Chen ◽  
Yue Shen ◽  
Jiahui Li ◽  
Yi Dong
Keyword(s):  
Femoral Artery ◽  
Lower Limb ◽  
Axillary Artery ◽  
Type A ◽  
Lower Limbs ◽  
Acute Type ◽  
Ischemic Time ◽  
Aortic Repair ◽  
The Right ◽  
Artery Perfusion

Abstract Background Lower limb malperfusion accompanied with acute type A dissection (AAD) is reported to be an independent predictor for mortality. Timely treatment is required. However, staged approach to restore the perfusion of the ischemic leg before aortic repair has a continuously increase risk of aortic rupture. Aortic repair under isolated axillary artery perfusion also has the risk of prolonging leg ischemia. Here we introduce our experience in performing axillo-femoral perfusion, which is supposed to bring benefits for treating lower limb malperfuison. Methods Thirty patients who suffered AAD accompanied by lower limb ischemia enrolled in our study. All patients received aortic repair as soon as possible using the modified axillo-femoral perfusion approach. The cardiopulmonary bypass and cooling started with the right axillary artery perfusion. Then the femoral artery of the ischemic side was exposed and sewn to a graft connected with another inflow cannula. The rectal temperature was about 31 °C when the femoral perfusion started. The perfusion of the ischemic legs preoperative was estimated after the surgery by the clinical signs, the saturation of the distal-limb, and computed tomography scan. Results Twenty-eight patients got good perfusion of the lower body after the surgery. Two patients received femoral-femoral artery bypass immediately after surgery because of the thrombosis in the right common iliac artery, without further injury. No peripheral vessels damage occurred, and no compartment fasciotomy or amputation needed. One patient died for the sepsis and the subsequent multi organ failure 28 days postoperative. Conclusions The modified axllio-femoral perfusion could restore the lower limbs’ perfusion simultaneously during the aortic surgery without neither delaying dissection repair nor prolonging the ischemic time. It is a simple, but safe and effective technique.

scholarly journals Low Level LASER Therapy Induces Therapeutic Angiogenesis in Diabetic Mice with Hindlimb Ischemia

2018 ◽  
Author(s):  
Shi-Jie Huang ◽  
Yi-Hsien Teng ◽  
Yu-Jung Cheng
Keyword(s):  
Laser Treatment ◽  
Femoral Artery ◽  
Capillary Density ◽  
Therapeutic Angiogenesis ◽  
Low Level Laser Therapy ◽  
Diabetic Mice ◽  
Artery Ligation ◽  
Low Level ◽  
Low Level Laser ◽  
Level Laser

Patients with diabetes mellitus (DM) are at high risk of developing peripheral arterial obstructive disease (PAOD) in lower extremities. Previous studies show low level LASER therapy (LLLT) can increase angiogenesis in vivo and in vitro. Here we performed hindlimb ischemia as PAOD model on diabetic mice to test the effects of LLLT. Twenty C57Bl/6 mice were randomly divided into four groups. Control group mice received femoral artery ligation/excision only. DM group mice were injected with Streptozocin (STZ) to induce diabetes followed by femoral artery ligation/excision. LLLT group mice received femoral artery ligation/excision and the lower limbs received LASER treatment for five days (660nm, 10 min, 1.91 J/cm2) started from second day postoperatively. DM+LLLT group mice were received femoral artery ligation/excision and LASER treatment after diabetes induced. Three days after LASER treatment finished, limb blood flow was measured by Laser Doppler perfusion imaging. Capillary density was assessed by immunofluorescence staining. CD31, VEGF, HIF-1?, phospho-ERK, iNOS and eNOS protein level was examined by Western blot. Blood perfusion, capillary density, CD31, and VEGF protein levels were significantly higher in those groups received LLLT compared to control and DM group. Low level LASER significantly increased ERK phosphorylation and HIF-1? expression. In addition, phospho-eNOS was increased but iNOS protein level was decreased in mice received LASER treatment. In summary, the ability of low level LASER to induce therapeutic angiogenesis in diabetic mice suggested this approach deserves investigation as a novel approach to treat PAOD patients.

Role of early growth response 1 in arteriogenesis: Impact on vascular cell proliferation and leukocyte recruitment in vivo

2012 ◽  
Vol 107 (03) ◽  
pp. 562-574 ◽  
Author(s):  
Tibor Ziegelhoeffer ◽  
Matthias Heil ◽  
Silvia Fischer ◽  
Borja Fernández ◽  
Wolfgang Schaper ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Femoral Artery ◽  
Growth Response ◽  
Early Growth ◽  
Leukocyte Recruitment ◽  
Artery Ligation ◽  
Vascular Cell ◽  
Early Growth Response ◽  
Early Growth Response 1

SummaryBased on previous findings that early growth response 1 (Egr-1) participates in leukocyte recruitment and cell proliferation in vitro, this study was designed to investigate its mode of action during arteriogenesis in vivo. In a model of peripheral arteriogenesis, Egr-1 was significantly upregulated in growing collaterals of wild-type (WT) mice, both on mRNA and protein level. Egr-1−/− mice demonstrated delayed arteriogenesis after femoral artery ligation. They further showed increased levels of monocytes and granulocytes in the circulation, but reduced levels in adductor muscles under baseline conditions. After femoral artery ligation, elevated numbers of macrophages were detected in the perivascular zone of collaterals in Egr-1−/− mice and mRNA of leukocyte recruitment mediators was upregulated. Other Egr family members (Egr-2 to -4) were significantly upregulated only in Egr-1−/− mice, suggesting a mechanism of counterbalancing Egr-1 deficiency. Moreover, splicing factor-1, downregulated in WT mice after femoral artery ligation in the process of increased vascular cell proliferation, was upregulated in Egr-1−/− mice. αSM-actin on the other hand, significantly downregulated in WT mice, showed no differential expression in Egr-1−/− mice. While cell cycle regulator cyclin E and cdc20 were upregulated in Egr-1−/− mice, cyclin D1 expression decreased below the detection limit in collaterals, and the proliferation marker ki67 was not differentially expressed. In conclusion, compensation for deficiency in Egr-1 function in leukocyte recruitment can presumably be mediated by other transcription factors; however, Egr-1 is indispensable for effective vascular cell cycle progression in arteriogenesis.

Abstract 3645: RAGE Impairs Angiogenesis Consequent to Femoral Artery Ligation in Diabetic Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xiaoping Shen ◽  
Dmitri Belov ◽  
Rosa Rosario ◽  
Yoshifumi Naka ◽  
Ann Marie Schmidt ◽  
...  
Keyword(s):  
Blood Flow ◽  
Muscle Tissue ◽  
Femoral Artery ◽  
Advanced Glycation Endproducts ◽  
Peripheral Vasculature ◽  
Artery Ligation ◽  
Tissue Ischemia ◽  
Glycation Endproducts ◽  
Soluble Rage

The Receptor for Advanced Glycation Endproducts (RAGE) is implicated in the pathogenesis of diabetic complications. Previous studies illustrated that blockade/genetic deletion of RAGE prevented aberrant neointimal expansion in atherosclerosis and carotid artery balloon injury. Here, we tested the hypothesis that RAGE would contribute to impaired revascularization in the setting of acute femoral artery (FA) ligation, especially in diabetes. Wild type (WT) and RAGE −/− mice were rendered diabetic (D) with streptozotocin (stz); non-diabetic (ND) cohorts were treated with buffer alone. RAGE antigen (Western blotting) was upregulated ≈2.1 fold in the ipsilateral muscle tissue of animals subjected to arterial ligation beginning on day 3 and persisting through 28 days post-operatively; confocal microscopy localized RAGE expression to cells expressing CD31 (EC) and SM actin (SMC). A key proinflammatory RAGE ligand, S100B, was highly upregulated (Western blot) in the ipsilateral muscle tissue from day 1 through 14 after ligation and localized to cells expressing CD45 (inflammatory) and vascular cells (expressing CD31 and SMA). To test the role of RAGE in FA ligation, ND and D mice were subjected to surgery; immediately after surgery, animals received either RAGE ligand-binding decoy soluble RAGE (sRAGE), 200 μg, i/p per day for 7 days) or vehicle, PBS. In D mice, administration of sRAGE resulted in improved blood flow ratios on days 3 and 7 after FA ligation vs. vehicle ( p <0.01). To dissect the particular role of RAGE, we tested homozygous RAGE null mice. Both ND and D RAGE −/− mice displayed improved blood flow ratios (laser Doppler) on days 28 after FA ligation compared to ND and D WT mice ( p <0.05 & p <0.01). Immunohistochemistry staining with CD31 on ipsilateral muscle tissue demonstrated significantly increased microvessel density in D RAGE −/− mice on days 28 after FA ligation compared to D WT mice ( p <0.001). Together, these data link the ligand/RAGE axis to impaired vascular responses consequent to severe tissue ischemia in the peripheral vasculature, particularly in diabetes.

Abstract 533: Shear-Induced Collateral Artery Growth Modulated by Endoglin but Not by ALK1

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Margreet R de Vries ◽  
Leonard Seghers ◽  
Imo E Hoefer ◽  
Evangelia Pardali ◽  
Beerend P Hierck ◽  
...  
Keyword(s):  
Blood Flow ◽  
Shear Stress ◽  
Hind Limb ◽  
Limb Ischemia ◽  
Capillary Density ◽  
Artery Ligation ◽  
Laser Doppler Perfusion Imaging ◽  
Collateral Artery

Introduction: TGF- β stimulates both shear stress induced arteriogenesis and ischemia induced angiogenesis, by signaling through different receptors. In this study the role of TGF-β receptors ALK1 and endoglin is assessed in a murine model for hind limb ischemia induced neovascularization. Methods and Results: Femoral artery ligation was performed in mice heterozygous for either endoglin, or ALK1 and littermate controls. Blood flow recovery, monitored by laser doppler perfusion imaging, was significantly hampered in both endoglin and ALK1 heterozygous mice compared to controls by maximal 40% and 49%, respectively. Collateral artery size was significantly reduced in endoglin heterozygous mice compared to controls, but not in ALK1 heterozygous mice. Capillary density in ischemic calf muscles was unaffected, but capillaries from endoglin and ALK1 heterozygous mice were significantly larger when compared to controls. Furthermore, both endoglin and ALK1 heterozygous mice showed significant more erythrocyte extravasation near the capillaries than their littermate controls, pointing towards less mature capillaries. Murine endothelial cells were exposed to shear stress in vitro to study the differential role of endoglin and ALK1 in shear induced neovascularization. This resulted in high levels of endoglin messengerRNA, but not of ALK1. Conclusion: Here we demonstrated that both endoglin and ALK1 play a crucial role in blood flow recovery. Importantly, endoglin is essential in both shear induced collateral artery growth and in ischemia induced angiogenesis, whereas ALK1 is only involved in ischemia induced angiogenesis.

scholarly journals What Is Currently the Role of TcPO2 in the Choice of the Amputation Level of Lower Limbs? A Comprehensive Review

2021 ◽  
Vol 10 (7) ◽  
pp. 1413
Author(s):  
Judith Catella ◽  
Anne Long ◽  
Lucia Mazzolai
Keyword(s):  
Arterial Disease ◽  
Major Amputation ◽  
Lower Limbs ◽  
Limb Amputation ◽  
Quality Of Data ◽  
Amputation Level ◽  
Increased Risk ◽  
Transcutaneous Oximetry ◽  
Peripheral Arterial

Some patients still require major amputation for lower extremity peripheral arterial disease treatment. The purpose of pre-operative amputation level selection is to determine the most distal amputation site with the highest healing probability without re-amputation. Transcutaneous oximetry (TcPO2) can detect viable tissue with the highest probability of healing. Several factors affect the accuracy of TcPO2; nevertheless, surgeons rely on TcPO2 values to determine the optimal amputation level. Background about the development of TcPO2, methods of measurement, consequences of lower limb amputation level, and the place of TcPO2 in the choice of the amputation level are reviewed herein. Most of the retrospective studies indicated that calf TcPO2 values greater than 40 mmHg were associated with a high percentage of successful wound healing after below-knee-amputation, whereas values lower than 20 mmHg indicated an increased risk of unsuccessful healing. However, a consensus on the precise cut-off value of TcPO2 necessary to assure healing is missing. Ways of improvement for TcPO2 performance applied to the optimization of the amputation-level are reported herein. Further prospective data are needed to better approach a TcPO2 value that will promise an acceptable risk of re-amputation. Standardized TcPO2 measurement is crucial to ensure quality of data.

scholarly journals Endothelial deletion of PKCδ prevents VEGF inhibition and restores blood flow reperfusion in diabetic ischemic limb

2021 ◽  
Vol 18 (2) ◽  
pp. 147916412199903
Author(s):  
Laura Croteau ◽  
Clément Mercier ◽  
Étienne Fafard-Couture ◽  
Alexandre Nadeau ◽  
Stéphanie Robillard ◽  
...  
Keyword(s):  
Blood Flow ◽  
Phosphatase Activity ◽  
Capillary Density ◽  
Artery Ligation ◽  
Vegf Signaling ◽  
Post Surgery ◽  
Src Homology ◽  
Artery Disease ◽  
Ischemic Muscle

Aims: Peripheral artery disease is a complication of diabetes leading to critical hindlimb ischemia. Diabetes-induced inhibition of VEGF actions is associated with the activation of protein kinase Cδ (PKCδ). We aim to specifically investigate the role of PKCδ in endothelial cell (EC) function and VEGF signaling. Methods: Nondiabetic and diabetic mice, with ( ec-Prkcd−/−) or without ( ec-Prkcdf/f) endothelial deletion of PKCδ, underwent femoral artery ligation. Blood flow reperfusion was assessed up to 4 weeks post-surgery. Capillary density, EC apoptosis and VEGF signaling were evaluated in the ischemic muscle. Src homology region 2 domain-containing phosphatase-1 (SHP-1) phosphatase activity was assessed in vitro using primary ECs. Results: Ischemic muscle of diabetic ec-Prkcdf/f mice exhibited reduced blood flow reperfusion and capillary density while apoptosis increased as compared to nondiabetic ec-Prkcdf/f mice. In contrast, blood flow reperfusion and capillary density were significantly improved in diabetic ec-Prkcd−/− mice. VEGF signaling pathway was restored in diabetic ec-Prkcd−/− mice. The deletion of PKCδ in ECs prevented diabetes-induced VEGF unresponsiveness through a reduction of SHP-1 phosphatase activity. Conclusions: Our data provide new highlights in mechanisms by which PKCδ activation in EC contributed to poor collateral vessel formation, thus, offering novel therapeutic targets to improve angiogenesis in the diabetic limb.

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