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Current evidence suggests that endothelial progenitor cells (EPC) contribute to ischemic tissue repair by both secretion of paracrine factors and incorporation into developing vessels. We tested the hypothesis that cell-free administration of paracrine factors secreted by cultured EPC may achieve an angiogenic effect equivalent to cell therapy. EPC-derived conditioned medium (EPC-CM) was obtained from culture expanded EPC subjected to 72 hours of hypoxia. In vitro, EPC-CM significantly inhibited apoptosis of mature endothelial cells and promoted angiogenesis in a rat aortic ring assay. The therapeutic potential of EPC-CM as compared to EPC transplantation was evaluated in a rat model of chronic hindlimb ischemia. Serial intramuscular injections of EPC-CM and EPC both significantly increased hindlimb blood flow assessed by laser Doppler (81.2+/-2.9% and 83.7+/-3.0% vs. 53.5+/-2.4% of normal, P<0.01) and improved muscle performance. A significantly increased capillary density (1.62+/-0.03 and 1.68+/-0.05/muscle fiber, P<0.05), enhanced vascular maturation (8.6+/-0.3 and 8.1+/-0.4/HPF, P<0.05) and muscle viability corroborated the findings of improved hindlimb perfusion and muscle function. Furthermore, EPC-CM transplantation stimulated the mobilization of bone marrow (BM)-derived EPC compared to control (678.7+/-44.1 vs. 340.0+/-29.1 CD34(+)/CD45(-) cells/1x10(5) mononuclear cells, P<0.05) and their recruitment to the ischemic muscles (5.9+/-0.7 vs. 2.6+/-0.4 CD34(+) cells/HPF, P<0.001) 3 days after the last injection. Intramuscular injection of EPC-CM is as effective as cell transplantation for promoting tissue revascularization and functional recovery. Owing to the technical and practical limitations of cell therapy, cell free conditioned media may represent a potent alternative for therapeutic angiogenesis in ischemic cardiovascular diseases.

Animal studies and preliminary results in humans suggest that lower extremity and myocardial ischemia can be attenuated by treatment with angiogenic cytokines. The resident population of endothelial cells that is competent to respond to an available level of angiogenic growth factors, however, may potentially limit the extent to which cytokine supplementation enhances tissue neovascularization. Accordingly, we transplanted human endothelial progenitor cells (hEPCs) to athymic nude mice with hindlimb ischemia. Blood flow recovery and capillary density in the ischemic hindlimb were markedly improved, and the rate of limb loss was significantly reduced. Ex vivo expanded hEPCs may thus have utility as a \"supply-side\" strategy for therapeutic neovascularization.

Endothelial progenitor cells (EPCs) have been isolated from circulating mononuclear cells in human peripheral blood and shown to be incorporated into foci of neovascularization, consistent with postnatal vasculogenesis 1 . We determined whether endogenous stimuli (tissue ischemia) and exogenous cytokine therapy (granulocyte macrophage-colony stimulating factor, GM-CSF) mobilize EPCs and thereby contribute to neovascularization of ischemic tissues. The development of regional ischemia in both mice and rabbits increased the frequency of circulating EPCs. In mice, the effect of ischemia-induced EPC mobilization was demonstrated by enhanced ocular neovascularization after cornea micropocket surgery in mice with hindlimb ischemia compared with that in non-ischemic control mice. In rabbits with hindlimb ischemia, circulating EPCs were further augmented after pretreatment with GM-CSF, with a corresponding improvement in hindlimb neovascularization. There was direct evidence that EPCs that contributed to enhanced corneal neovascularization were specifically mobilized from the bone marrow in response to ischemia and GM-CSF in mice transplanted with bone marrow from transgenic donors expressing β-galactosidase transcriptionally regulated by the endothelial cell-specific Tie-2 promoter. These findings indicate that circulating EPCs are mobilized endogenously in response to tissue ischemia or exogenously by cytokine therapy and thereby augment neovascularization of ischemic tissues.

Background Venous leak appears to be the most common cause of vasculogenic erectile dysfunction (ED), which can be treated with venous embolization. Traditionally, conventional cavernosography was used for the diagnosis and treatment planning of venous leak. Recently, computed tomography (CT) cavernosography was introduced as a novel cross-sectional imaging method proposed to be advantageous over conventional cavernosography. We created a novel management algorithm for diagnosing venous leak including CT cavernosography as an imaging modality. In order to provide a broader basis for our management algorithm, a systematic literature review was conducted. Main body In this article we systematically review relevant literature on using CT cavernosography for the diagnosis and treatment planning in ED patients with venous leak following the PRISMA selection process. Nine full-text articles were included in the review and assigned a level of evidence grade (all grade II). Two studies (2/9) compared the results of conventional cavernosography with those of CT cavernosography which was superior for site-specific venous leak identification (19.4% vs. 100%, respectively). CT cavernosography is a more detailed imaging method that is faster to perform, exposes the patient to less radiation, and requires less contrast material. In one study (1/9), CT cavernosography was used for diagnostic purposes only. Eight studies (8/9) cover both, diagnostic imaging and treatment planning including embolization (1/9) and sclerotherapy (2/9) of venous leak in patients with venogenic ED. Three studies (3/9) describe anatomical venous leak classifications that were established based on CT cavernosography findings for accurate mapping of superficial and/or deep venous leak and identification of mixed or more complex forms of venous leak present in up to 84% of patients. In addition to treatment planning, one study (1/9) used CT cavernosography also for follow-up imaging post treatment. Conclusion CT cavernosography is superior to conventional cavernosography for diagnosis and treatment planning in patients with ED caused by venous leak (grade II levels of evidence). Consequently, CT cavernosography should be included in management algorithms for ED patients with suspected venous leak.

Objectives We investigated whether qualitative or quantitative alterations of the endothelial progenitor cell (EPC) pool predict age-related structural vessel wall changes. Background We have previously shown that age-related endothelial dysfunction is accompanied by qualitative rather than quantitative changes of EPCs. Animal studies suggest that impaired EPC functions lead to accelerated arterial intimal thickening. Methods Intima-media thickness (IMT) was measured in the common carotid artery in our previously published groups of younger (25 ± 1 years, n  = 20) and older (61 ± 2 years, n  = 20) healthy non-smoking volunteers without arterial hypertension, hypercholesterolemia, and diabetes mellitus. Endothelial progenitor cells (EPCs, KDR + /CD34 + and KDR + /CD133 + ) were counted in peripheral blood using flow cytometry. In ex vivo expanded EPCs, the function was determined as chemotaxis to VEGF, proliferation, and survival. Results We observed thicker IMT in older as compared to younger subjects (0.68 ± 0.03 mm Vs. 0.48 ± 0.02 mm, P  < 0.001). Importantly, there were significant inverse univariate correlations between IMT, EPC chemotaxis, and survival ( r  = −0.466 P  < 0.05; r  = −0.463, P  < 0.01). No correlation was observed with numbers of circulating EPCs. Multivariate regression analysis revealed that age, mean arterial pressure and migration of EPCs were independent predictors of IMT ( R 2  = 0.58). Conclusion Impaired EPC function may lead to accelerated vascular remodeling due to chronic impairment of endothelial maintenance.

Endothelial Progenitor Cells (EPC) support neovascularization and regeneration of injured endothelium both by providing a proliferative cell pool capable of differentiation into mature vascular endothelial cells and by secretion of angiogenic growth factors. The aim of this study was to investigate the role of PDGF-BB and PDGFRβ in EPC-mediated angiogenesis of differentiated endothelial cells. Conditioned medium from human EPC (EPC-CM) cultured in hypoxic conditions contained substantially higher levels of PDGF-BB as compared to normoxic conditions (P<0.01). EPC-CM increased proliferation (1.39-fold; P<0.001) and migration (2.13-fold; P<0.001) of isolated human umbilical vein endothelial cells (HUVEC), as well as sprouting of vascular structures from ex vivo cultured aortic rings (2.78-fold increase; P = 0.01). The capacity of EPC-CM to modulate the PDGFRβ expression in HUVEC was assessed by western blot and RT-PCR. All the pro-angiogenic effects of EPC-CM on HUVEC could be partially inhibited by inactivation of PDGFRβ (P<0.01). EPC-CM triggered a distinct up-regulation of PDGFRβ (2.5±0.5; P<0.05) and its phosphorylation (3.6±0.6; P<0.05) in HUVEC. This was not observed after exposure of HUVEC to recombinant human PDGF-BB alone. These data indicate that EPC-CM sensitize endothelial cells and induce a pro-angiogenic phenotype including the up-regulation of PDGFRβ, thereby turning the PDGF/PDGFRβ signaling-axis into a critical element of EPC-induced endothelial angiogenesis. This finding may be utilized to enhance EPC-based therapy of ischemic tissue in future.

Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an alpha-helix configuration. In this paper we look at the immune response of CD8(+) T cells to ZPSs. Intraperitoneal application of the ZPS Sp1 from Streptococcus pneumoniae serotype 1 induces CD8(+)CD28(-) T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Sp1 (mSp1) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD8(+)CD28(-) T lymphocytes. The Sp1-induced CD8(+)CD28(-) T lymphocytes are CD122(low)CTLA-4(+)CD39(+). They synthesize IL-10 and TGF-beta. The Sp1-induced CD8(+)CD28(-) T cells exhibit immunosuppressive properties on CD4(+) T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD8(+) T cell activation by Sp1 demonstrate in a dimeric MHC class I-Ig model that Sp1 induces CD8(+) T cell activation by enhancing crosslinking of TCR. The expansion of CD8(+)CD28(-) T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD8(+)CD28(-) T cells, Sp1 enhances Zap-70 phosphorylation and increasingly involves NF-kappaB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD8(+)CD28(-) population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD8(+)CD28(-) T lymphocytes in vivo and in vitro. The underlying mechanism of CD8(+) T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system.

To analyze the safety and efficacy of additional venous leak embolization after an initial arterial revascularization to treat patients with combined arteriogenic and venogenic erectile dysfunction (ED). Single-center observational study from October 1, 2019, to September 30, 2022, including 26 patients with ED resistant to phosphodiesterase-5-inhibitors (PDE5i) and without significant clinical benefit after arterial revascularization of erection-related arteries. Additional treatment with venous leak embolization was performed 458 ± 424 days after arterial revascularization. Arterial obstruction and venous leak were verified based on color Doppler flow analysis, computed tomography angiography, and computed tomography cavernosography. The primary safety endpoint was any major adverse event 6 weeks after the procedure. The primary feasibility endpoint was defined as an IIEF-6 (International Index of Erectile Function-6) score improvement of ≥ 4 points at 6-week follow-up post intervention. Procedural success was achieved in all patients with no major adverse events on follow-up. The primary feasibility endpoint at 6-week follow-up was reached with 3/26 (11.5%) of patients following arterial revascularization only. Six weeks after additional venous embolization, the primary feasibility endpoint was reached in 17/26 (65.4%) of patients. Venous leak embolization yields additional clinical improvement and treatment potential in patients with vasculogenic ED not responding to PDE5i due to mixed arterio-venous disease and insufficient clinical improvement after arterial revascularization alone.

Purpose To analyze the safety and efficacy of additional venous leak embolization after an initial arterial revascularization to treat patients with combined arteriogenic and venogenic erectile dysfunction (ED). Materials and Methods Single-center observational study from October 1, 2019, to September 30, 2022, including 26 patients with ED resistant to phosphodiesterase-5-inhibitors (PDE5i) and without significant clinical benefit after arterial revascularization of erection-related arteries. Additional treatment with venous leak embolization was performed 458 ± 424 days after arterial revascularization. Arterial obstruction and venous leak were verified based on color Doppler flow analysis, computed tomography angiography, and computed tomography cavernosography. The primary safety endpoint was any major adverse event 6 weeks after the procedure. The primary feasibility endpoint was defined as an IIEF-6 (International Index of Erectile Function-6) score improvement of ≥ 4 points at 6-week follow-up post intervention. Results Procedural success was achieved in all patients with no major adverse events on follow-up. The primary feasibility endpoint at 6-week follow-up was reached with 3/26 (11.5%) of patients following arterial revascularization only. Six weeks after additional venous embolization, the primary feasibility endpoint was reached in 17/26 (65.4%) of patients. Conclusion Venous leak embolization yields additional clinical improvement and treatment potential in patients with vasculogenic ED not responding to PDE5i due to mixed arterio-venous disease and insufficient clinical improvement after arterial revascularization alone. Graphical Abstract

Purpose To angiographically evaluate infrapopliteal arterial lesion morphology in a consecutive series of patients presenting with critical limb ischemia (CLI) and undergoing infrapopliteal angioplasty. Methods A prospective analysis was undertaken of a consecutive series of CLI patients undergoing endovascular therapy in a tertiary referral center in the year 2011. Morphological assessment of baseline angiograms obtained prior to revascularization included lesion length, assessment of calcification using a semi-quantitative scoring system, and reference vessel diameter (RVD) measurement. Delta RVDs were assessed subtracting distal RVDs from proximal RVDs. A total of 197 infrapopliteal lesions in 105 CLI patients (n=106 limbs) were assessed. Of these, 136 lesions were treated by endovascular means. Results The average length of treated lesions was 87.1±43.8 mm in stenoses and 124.0±78.3 mm in chronic occlusions (p<0.001). Mean RVD proximal to the lesions was 1.88 mm whereas it was 1.66 mm distal to the lesions (p≤0.03). Mean arterial calcification was 1.15. Conclusion This prospective angiographic series underlines the complex nature and extensive longitudinal involvement of infrapopliteal lesions in CLI patients. These findings should be taken into consideration for anti-restenosis concepts in this challenging subgroup of peripheral artery disease patients.