P0144LOW-ENERGY SHOCKWAVE TREATMENT PROMOTES ENDOTHELIAL PROGENITOR CELL HOMING TO THE STENOTIC PIG KIDNEY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Yu Zhao ◽  
Xiao liang Zhang ◽  
Bicheng Liu ◽  
Lilach Lerman
Keyword(s):  
Endothelial Cell ◽  
Renal Artery ◽  
Ex Vivo ◽  
Vena Cava ◽  
Capillary Density ◽  
Low Energy ◽  
Swine Model ◽  
Endothelial Progenitor ◽  
Atherosclerotic Renal Artery Stenosis ◽  
Shockwave Therapy

Abstract Background and Aims Endothelial progenitor cells (EPCs) patrol the circulation and contribute to endothelial cell regeneration and tissue revascularization. Atherosclerotic renal artery stenosis (ARAS) induces microvascular loss in the stenotic kidney. A regimen of low–energy shockwave therapy (SW) induces angiogenesis and reduces chronic ischemia, but the mechanism remains unclear. This study tested the hypothesis that SW increases EPCs homing to the stenotic kidney and increases renal capillary regeneration in a unilateral ARAS swine model. Method Domestic pigs were randomized to normal control or unilateral ARAS (induced by a local irritant coil in the renal artery and a high-fat diet). ARAS pigs were treated with low-energy SW (0.1 mJ/mm2) or sham (n=6 each group), bi-weekly for 3 consecutive weeks, starting after 3 weeks of ARAS. Blood samples for EPCs (CD34+ and KDR+ by flow cytometry) and the homing factor SDF-1 were collected 4 weeks after completion of SW treatment from the inferior vena cava (IVC) and the stenotic kidney (STK) vein and artery. Urine was collected from the urinary bladder. Kidneys were studied ex vivo for morphology and expression of an endothelial cell marker (CD31) and the pro- angiogenic growth factor angiopoietin (Ang)-1. Results In ARAS, tubulointerstitial fibrosis, tubular score, urinary protein, serum creatinine and mean arterial pressure were significantly increased and capillary count (Fig. 1A) decreased (P<0.05 vs. control), but all markedly improved in ARAS+SW (P<0.05 vs. ARAS). EPC number was decreased in the IVC and renal artery of ARAS pigs (Fig. 1B), but improved in ARAS+SW. SDF-1 levels in the IVC, STK vein and artery, and Ang-1 expression in the kidney of ARAS+SW, were all increased (P<0.05 vs. ARAS). Conclusion Low-energy shockwave improves ischemic kidney capillary density, which is associated with and may be at least in part mediated by promoting EPC mobilization and homing to the stenotic kidney.

scholarly journals Low-Energy Shockwave Treatment Promotes Endothelial Progenitor Cell Homing to the Stenotic Pig Kidney

2020 ◽  
Vol 29 ◽  
pp. 096368972091734 ◽  
Author(s):  
Yu Zhao ◽  
Adrian Santelli ◽  
Xiang-Yang Zhu ◽  
Xin Zhang ◽  
John R. Woollard ◽  
...  
Keyword(s):  
Renal Artery ◽  
Renal Artery Stenosis ◽  
Ex Vivo ◽  
Vena Cava ◽  
Underlying Mechanism ◽  
Low Energy ◽  
Artery Stenosis ◽  
Endothelial Progenitor ◽  
Atherosclerotic Renal Artery Stenosis ◽  
Urinary Levels

Endothelial progenitor cells (EPCs) patrols the circulation and contributes to endothelial cell regeneration. Atherosclerotic renal artery stenosis (ARAS) induces microvascular loss in the stenotic kidney (STK). Low-energy shockwave therapy (SW) can induce angiogenesis and restore the STK microcirculation, but the underlying mechanism remains unclear. We tested the hypothesis that SW increases EPC homing to the swine STK, associated with capillary regeneration. Normal pigs and pigs after 3 wk of renal artery stenosis were treated with six sessions of low-energy SW (biweekly for three consecutive weeks) or left untreated. Four weeks after completion of treatment, we assessed EPC (CD34+/KDR+) numbers and levels of the homing-factor stromal cell-derived factor (SDF)-1 in the inferior vena cava and the STK vein and artery, as well as urinary levels of vascular endothelial growth factor (VEGF) and integrin-1β. Subsequently, we assessed STK morphology, capillary count, and expression of the proangiogenic growth factors angiopoietin-1, VEGF, and endothelial nitric oxide synthase ex vivo. A 3-wk low-energy SW regimen improved STK structure, capillary count, and function in ARAS+SW, and EPC numbers and gradients across the STK decreased. Plasma SDF-1 and renal expression of angiogenic factors were increased in ARAS+SW, and urinary levels of VEGF and integrin-1β tended to rise during the SW regimen. In conclusion, SW improves ischemic kidney capillary density, which is associated with, and may be at least in part mediated by, promoting EPCs mobilization and homing to the stenotic kidney.

scholarly journals Mesenchymal Stem Cell-Derived Extracellular Vesicles Improve the Renal Microvasculature in Metabolic Renovascular Disease in Swine

2018 ◽  
Vol 27 (7) ◽  
pp. 1080-1095 ◽  
Author(s):  
Alfonso Eirin ◽  
Xiang-Yang Zhu ◽  
Sreela Jonnada ◽  
Amir Lerman ◽  
Andre J. van Wijnen ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Capillary Density ◽  
Swine Model ◽  
Renovascular Disease ◽  
And Function ◽  
Angiogenic Genes ◽  
Endothelial Growth Factor

Background: Extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) mediate their paracrine effect, but their efficacy to protect the microcirculation of the kidney is unknown. Using a novel swine model of unilateral renovascular disease (RVD) complicated by metabolic syndrome (MetS), we tested the hypothesis that EVs would attenuate renal microvascular loss. Methods: Four groups of pigs ( n = 7 each) were studied after 16 weeks of diet-induced MetS and RVD (MetS+RVD), MetS+RVD treated 4 weeks earlier with a single intra-renal delivery of EVs harvested from autologous adipose tissue-derived MSCs, and Lean and MetS Sham controls. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in-vivo (fast CT), whereas EV characteristics, renal microvascular architecture (micro-CT), and injury pathways were studied ex-vivo. Results: mRNA sequencing and proteomic analysis revealed that EVs are packed with several pro-angiogenic genes and proteins, such as vascular endothelial growth factor. Labeled EVs were detected in the stenotic kidney 4 weeks after injection internalized by tubular and endothelial cells. EVs restored renal expression of angiogenic factors and improved cortical microvascular and peritubular capillary density. Renal apoptosis, oxidative stress, tubular injury, and fibrosis were also attenuated in EV-treated pigs. RBF and GFR decreased in MetS+RVD compared with MetS, but normalized in MetS+RVD+EVs. Conclusions: Intra-renal delivery of MSC-derived EVs bearing pro-angiogenic properties restored the renal microcirculation and in turn hemodynamics and function in chronic experimental MetS+RVD. Our study suggests a novel therapeutic potential for MSC-derived EVs in restoring renal hemodynamics in experimental MetS+RVD.

scholarly journals Western diet induces renal artery endothelial stiffening that is dependent on the epithelial Na+ channel

2020 ◽  
Vol 318 (5) ◽  
pp. F1220-F1228 ◽  
Author(s):  
Yuxin Xiong ◽  
Annayya R. Aroor ◽  
Francisco I. Ramirez-Perez ◽  
Guanghong Jia ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Renal Artery ◽  
Ex Vivo ◽  
Oxidant Stress ◽  
Western Diet ◽  
Na Channel ◽  
Renal Circulation ◽  
Α Subunit ◽  
Arterial Stiffening ◽  
Vascular Stiffening

Consumption of a Western diet (WD) induces central aortic stiffening that contributes to the transmittance of pulsatile blood flow to end organs, including the kidney. Our recent work supports that endothelial epithelial Na+ channel (EnNaC) expression and activation enhances aortic endothelial cell stiffening through reductions in endothelial nitric oxide (NO) synthase (eNOS) and bioavailable NO that result in inflammatory and oxidant responses and perivascular fibrosis. However, the role that EnNaC activation has on endothelial responses in the renal circulation remains unknown. We hypothesized that cell-specific deletion of the α-subunit of EnNaC would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Twenty-eight-week-old female αEnNaC knockout and wild-type mice were fed either mouse chow or WD containing excess fat (46%), sucrose, and fructose (17.5% each). WD feeding increased fat mass, indexes of vascular stiffening in the aorta and renal artery (in vivo pulse wave velocity and ultrasound), and renal endothelial cell stiffening (ex vivo atomic force microscopy). WD further impaired aortic endothelium-dependent relaxation and renal artery compliance (pressure myography) without changes in blood pressure. WD-induced renal arterial stiffening occurred in parallel to attenuated eNOS activation, increased oxidative stress, and aortic and renal perivascular fibrosis. αEnNaC deletion prevented these abnormalities and support a novel mechanism by which WD contributes to renal arterial stiffening that is endothelium and Na+ channel dependent. These results demonstrate that cell-specific EnNaC is important in propagating pulsatility into the renal circulation, generating oxidant stress, reduced bioavailable NO, and renal vessel wall fibrosis and stiffening.

scholarly journals Endothelial Progenitor Cells Augment Collateralization and Hemodynamic Rescue in a Model of Chronic Cerebral Ischemia

2014 ◽  
Vol 34 (8) ◽  
pp. 1297-1305 ◽  
Author(s):  
Nils Hecht ◽  
Ulf C Schneider ◽  
Marcus Czabanka ◽  
Maria Vinci ◽  
Antonis K Hatzopoulos ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Capillary Density ◽  
Cerebral Hypoperfusion ◽  
Endothelial Progenitor ◽  
Vessel Occlusion ◽  
Cerebrovascular Reserve ◽  
Cerebral Hemodynamic ◽  
Significant Impairment ◽  
Hemodynamic Impairment

Surgical flow augmentation for treatment of cerebral hemodynamic impairment remains controversial. Here, we investigated the benefit of endothelial progenitor cell (EPC) treatment in a rat model of chronic cerebral hypoperfusion. At repeated time points after 3-vessel occlusion (3-VO), animals were treated with 1 × 10 6 Dil-labeled (a) ex vivo-expanded embryonic-EPC (e-EPC), (b) cyclic AMP-differentiated embryonic-endothelial progenitor-derived cells (e-EPDC as biologic control) or, (c) saline. The cerebrovascular reserve capacity (CVRC) was assessed immediately before and on days 7 and 21 after 3-VO. Structural effects were assessed by latex perfusion, immunohistochemistry, and intravital fluorescence video microscopy on day 21. Three-vessel occlusion resulted in a significant impairment of the CVRC with better functional recovery after treatment with e-EPC (16.4 ± 8%) compared with e-EPDC (3.7 ± 8%) or saline (6.4 ± 9%) by day 21 ( P<0.05), which was paralleled by a significant increase in the vessel diameters of the anterior Circle of Willis, a significantly higher number of leptomeningeal anastomoses and higher parenchymal capillary density in e-EPC-treated animals. Interestingly, despite in vivo interaction of e-EPC with the cerebral endothelium, e-EPC incorporation into the cerebral vasculature was not observed. Our results suggest that EPC may serve as a novel therapeutic agent in clinical trials for nonsurgical treatment of chronic cerebral hemodynamic impairment.

The Effect of Pentosan Polysulphate (SP54) on the Fibrinolytic Enzyme System - A Human Volunteer and Experimental Animal Study

1985 ◽  
Vol 54 (04) ◽  
pp. 833-837 ◽  
Author(s):  
N A Marsh ◽  
P M Peyser ◽  
L J Creighton ◽  
M Mahmoud ◽  
P J Gaffney
Keyword(s):  
Plasminogen Activator ◽  
Surface Effect ◽  
Ex Vivo ◽  
Vena Cava ◽  
Tissue Type ◽  
Similar Response ◽  
Small Contribution ◽  
Thrombosis Model ◽  
Pentosan Polysulphate

SummaryPentosan polysulphate causes an increase in plasminogen activator activity in plasma both after oral ingestion and after subcutaneous injection. The effect is greatest after 3 h and has disappeared by 6 h. Repeat doses by mouth over 5 days elicit a similar response. The recorded increase in activity is due largely to the release of tissue-type plasminogen activator (tPA) from the endothelium according to the antigen assay although there could be a small contribution from Factor XH-related “intrinsic” fibrinolysis induced in vitro. SP54 enhances activity ex vivo by a non-specific surface effect, and this phenomenon may contribute the increased levels of activity seen in vitro. Administration of SP54 to animals elicits a similar increase in activator activity, the intramuscular route being slightly more effective. Results with an inferior vena cava thrombosis model in the rat suggest that pentosan polysulphate may induce a thrombolytic effect.

Organische Nitrate und Thrombozytenfunktion

1988 ◽  
Vol 08 (02) ◽  
pp. 90-99 ◽  
Author(s):  
H. Schröder ◽  
K. Schrör
Keyword(s):  
Endothelial Cell ◽  
Angina Pectoris ◽  
Ex Vivo

ZusammenfassungOrganische Nitrate unterschiedlicher chemischer Struktur sowie Nitroprussidnatrium und Molsidomin (bzw. ihre biologisch aktiven Metaboliten) können die (primäre) Aggregation und Sekretion von Humanthrombozyten in vitro und ex vivo hemmen. Eine solche Wirkung wird für Molsidomin (SIN-1) und Nitroprussidnatrium in vitro in Konzentrationen beobachtet, die in der gleichen Größenordnung liegen wie die vasodilatierenden Effekte der Substanzen. Dagegen sind für eine direkte Antiplättchenwirkung organischer Nitrate (Glyzeryltrinitrat, Isosorbiddinitr at, Isosorbidmononitrate, Teopranitol) in vitro Konzentrationen erforderlich, die ca. 100- bis 1000fach höher sind als die Plasmaspiegel der Substanzen nach therapeutischer Dosierung bzw. die Konzentrationen, die isolierte Gefäßstreifen relaxieren. Als gemeinsamer Wirkungsmechanismus der direkten thrombozy-tenfunktionshemmenden und gefäßerweiternden Wirkung all dieser Substanzen kann heute eine Stickoxid-(NO)-vermittelte Stimulation der cGMP-Bildung angenommen werden, das aus organischen Nitraten als »Pro-drug« entsteht. Die Freisetzung von NO, eines »endothelial cell-derived relaxing factors« (EDRF) aus Nitroprussidnatrium und SIN-1 erfolgt spontan. Dagegen erfordert die Freisetzung von NO aus organischen Nitraten einen enzymatischen Stoffwechselweg, der in isolierten Thrombozyten nicht vorhanden ist. Eine Antiplättchenwirkung organischer Nitrate in vivo bzw. ex vivo wird daher über die Stimulation eines endothelialen, thrombozyteninhibitorischen Faktors erklärt. Hierbei sind Prostazyklin sowie ein bisher unbekannter Endothel-zellfaktor neben einer synergistischen Wirkung organischer Nitrate mit endogenem Prostazyklin in Diskussion. Eine thrombozytenfunktionshemmen-de Wirkung organischer Nitrate könnte in Kombination mit ihren hämody-namischen Effekten auch für die an-tianginöse Wirkung in der Klinik bedeutsam sein, insbesondere zur Verhinderung vasospastischer Zustände bei der instabilen Angina pectoris.

Ex Vivo Repair of a Renal Artery Saccular Aneurysm in a Living-Nonrelated Donor and Subsequent Successful Kidney Transplantation

2018 ◽  
Vol 52 (6) ◽  
pp. 455-458
Author(s):  
Rogerio A. Muñoz-Vigna ◽  
Javier E. Anaya-Ayala ◽  
Juan N. Ramirez-Robles ◽  
Daniel Nuño-Diaz ◽  
Sandra Olivares-Cruz
Keyword(s):  
Kidney Transplantation ◽  
Renal Artery ◽  
Ex Vivo ◽  
Incidental Finding ◽  
Left Kidney ◽  
Renal Arteries ◽  
Saccular Aneurysm ◽  
Preoperative Imaging ◽  
The Right ◽  
Stage Renal Disease

The use of kidney grafts with aneurysmal disease involving the renal arteries for transplantation is very uncommon and relatively controversial. We herein present the case of a 52-year-old woman who volunteered to become a living-nonrelated donor; during the preoperative imaging workup, a computed tomography angiography revealed a 1.5-cm saccular aneurysm in the left kidney, while the contralateral renal artery was normal. We decided to utilize the left kidney for a 25-year-old male patient with end-stage renal disease, and following the ex vivo repair using the recipient epigastric vessels and saphenous veins, we completed the transplantation in the right pelvic fossa. The postoperative period was uneventful, and at 8 months from the surgery, the graft remains functional. The surgical repair of renal artery aneurysms followed by immediate kidney transplantation is a safe technique and an effective replacement therapy for recipients. The incidental finding of isolated aneurysmal disease in renal arteries should not exclude graft potential availability for transplantation following repair.

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