New recommendations on cerebral venous and dural sinus thrombosis from the German consensus-based (S2k) guideline.

Over the last years, new evidence has accumulated on multiple aspects of diagnosis and management of cerebral venous and dural sinus thrombosis (CVT) including identification of new risk factors, studies on interventional treatment as well as treatment with direct oral anticoagulants. Based on the GRADE questions of the European Stroke Organization guideline on this topic, the new German guideline on CVT is a consensus between expert representatives of Austria, Germany and Switzerland. New recommendations include:• CVT occurring in the first weeks after SARS-CoV-2 vaccination with vector vaccines may be associated with severe thrombocytopenia, indicating the presence of a prothrombotic immunogenic cause (Vaccine-induced immune thrombotic thrombocytopenia; VITT).• D-dimer testing to rule out CVT cannot be recommended and should therefore not be routinely performed.• Thrombophilia screening is not generally recommended in patients with CVT. It should be considered in young patients, in spontaneous CVT, in recurrent thrombosis and/or in case of a positive family history of venous thromboembolism, and if a change in therapy results from a positive finding.• Patients with CVT should preferably be treated with low molecular weight heparine (LMWH) instead of unfractionated heparine in the acute phase.• On an individual basis, endovascular recanalization in a neurointerventional center may be considered for patients who deteriorate under adequate anticoagulation.• Despite the overall low level of evidence, surgical decompression should be performed in patients with CVT, parenchymal lesions (congestive edema and/or hemorrhage) and impending incarceration to prevent death.• Following the acute phase, oral anticoagulation with direct oral anticoagulants instead of vitamin K antagonists should be given for 3 to 12 months to enhance recanalization and prevent recurrent CVT as well as extracerebral venous thrombosis.• Women with previous CVT in connection with the use of combined hormonal contraceptives or pregnancy shall refrain from continuing or restarting contraception with oestrogen-progestagen combinations due to an increased risk of recurrence if anticoagulation is no longer used.• Women with previous CVT and without contraindications should receive LMWH prophylaxis during pregnancy and for at least 6 weeks post partum.Although the level of evidence supporting these recommendations is mostly low, evidence from deep venous thrombosis as well as current clinical experience can justify the new recommendations.This article is an abridged translation of the German guideline, which is available online.

Venous Leak Embolization in Patients with Venogenic Erectile Dysfunction via Deep Dorsal Penile Vein Access: Safety and Early Efficacy.

PURPOSE: This all-comers registry aimed to assess safety and early efficacy of venous embolization in patients with venogenic erectile dysfunction due to venous leak in an unselected cohort. METHODS: Between October 2019 and September 2022, patients with venogenic erectile dysfunction resistant to phosphodiesterase-5-inhibitors were treated with venous embolization using ultrasound-guided anterograde access via a deep dorsal penile vein in a single center. A mix of ethiodized oil and modified cyanoacrylate-based glue n-butyl 2 cyanoacrylate (NBCA) monomer plus methacryloxy-sulpholane monomer (Glubran-2, GEM, Italy) was used as liquid embolic agent. Prior to embolization, venous leak had been verified based on penile duplex sonography and computed tomography cavernosography. Procedural success was defined as technically successful and complete target vein embolization. The primary safety outcome measure was any major adverse event 6 weeks after the procedure. The primary feasibility outcome measure was IIEF-15 (International Index of Erectile Function-15) score improvement ≥ 4 points in ≥ 50% of subjects on 6 weeks follow-up post intervention. RESULTS: Fifty consecutive patients (mean age 61.8 ± 10.0 years) with severe erectile dysfunction due to venous leak underwent venous embolization. Procedural success was achieved in 49/50 (98%) of patients with no major adverse events on follow-up. The primary feasibility outcome measure at 6 weeks was reached by 34/50 (68%) of patients. CONCLUSION: Venous leak embolization via deep dorsal penile vein access using a liquid embolic agent was safe for all and efficacious in the majority of patients with severe venogenic erectile dysfunction on 6 weeks follow-up.

Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for 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. 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 beta-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.

Impact of long-term corticosteroid therapy on the distribution pattern of lower limb atherosclerosis.

OBJECTIVE: Ectopic calcification and mediacalcinosis can be promoted by corticosteroid use. Aim of the present investigation is to describe macrovascular disease features in patients with long-term corticosteroid therapy and symptomatic lower limb peripheral arterial occlusive disease (PAD). METHODS: A consecutive series of 2783 patients undergoing clinical and angiographic work-up of PAD were screened for long-term (>5 years) corticosteroid use (group A). Comparison was performed to a randomly selected age-, sex- and risk factor-matched PAD control cohort from the same series without corticosteroid use (group B). Patients with diabetes mellitus or severe renal failure were excluded. Arterial calcification was evaluated by qualitative assessment on radiographic images. Severity of atherosclerotic lesions was analysed from angiographic images using a semi-quantitative score (Bollinger score). RESULTS: In general, 12 patients (5 males, mean age 78.5 +/- 9.0 years) with 15 ischaemic limbs qualified to be enrolled in group A and were compared to 23 matching control patients (6 2 males, mean age 79.5 +/- 6 years) with 32 ischaemic limbs. Incompressibility of ankle arteries determined by measurement of the ankle-brachial index was seen in 12 limbs (80%) in group A compared to 3 limbs (9%) in group B (p = 0.0009). No significant difference was found comparing group A and B for segmental calcification, whereas comparison of the atherosclerotic burden using the angiographic severity score showed a significantly higher score at the infragenicular arterial level in group A (p = 0.001). CONCLUSION: Findings suggest that the long-term corticosteroid therapy is associated with a distally accentuated, calcifying peripheral atherosclerosis inducing arterial incompressibility. This occlusion pattern is comparable to patients with renal failure or diabetes. Further research is required to support our observations.

Distribution pattern of infrageniculate arterial obstructions in patients with diabetes mellitus and renal insufficiency - implications for revascularization.

BACKGROUND: Diabetes mellitus (DM) and renal insufficiency (RI) were shown to be associated with an obstructive lesion pattern favouring distal lower limb arterial segments in patients with peripheral arterial disease (PAD). We hypothesized that presence of DM is associated with pronounced involvement of the tibioperoneal arteries, whereas RI predominantly affects the pedal arch. PATIENTS AND METHODS: A consecutive series of PAD patients (mean age 75 +/- 10 years, 40 women) with RI alone (n = 15), RI and DM (n = 25), DM alone (n = 25) and without RI or DM (n = 25) underwent diagnostic angiography. We analyzed the obstructive burden of different segments of the infrageniculate arterial tree using the Bollinger score as well as accessibility of pedal arteries for bypass surgery. RESULTS: In patients with DM and in patients with RI the mean total obstructive burden was higher in pedal as compared to tibioperoneal arteries (9.79 +/- 4.60 vs. 6.99 +/- 3.45, p = 0.03;10.50 +/- 5.53 vs. 6.88 +/- 4.12, p = 0.05, respectively). However, rates of patency of at least one pedal artery were significantly lower in patients with RI and RI/DM as compared to controls (47% and 48% vs. 80%, respectively; p = 0.007), whereas patency was comparable between patients with diabetes alone and controls (72% vs. 80%, ns). Rates of viability of pedal arteries as an attachment site for distal bypass was 80%, 68%, 47% and 44% in controls, patients with DM alone, RI alone and RI/DM, respectively (p = 0.0042). CONCLUSIONS: In contrast to previous anecdotal observations, both DM and RI are associated with a high atherosclerotic burden of the pedal arch in the present angiographic series. The presence of RI, however, is associated with a lower patency of the pedal arch as compared to the presence of DM alone, and more than fifty percent patients are unsuitable for distal bypass grafting.

Long-term effects of supervised exercise training on walking capacity and quality of life in patients with intermittent claudication.

UNLABELLED: Supervised exercise training has been shown to improve walking capacity in several studies of patients with intermittent claudication. However, data on long-term outcome are quite limited. The aim of this prospective study was to evaluate long-term effects of supervised exercise training on walking capacity and quality of life in patients with intermittent claudication. PATIENTS AND METHODS: Sixty-seven consecutive patients with intermittent claudication who completed a supervised 12-week exercise training program were asked for follow up evaluation 39 +/- 20 months after program completion. Pain-free walking distance (PWD) and maximum walking distances (MWD) were assessed by treadmill test and several questionnaires. RESULTS: Forty (60%) patients agreed to participate, 22 (33%) refused participation, and 5 (7%) died during follow-up. PWD and MWD significantly improved at completion of 12-weeks supervised exercise training as compared to baseline (PWD 114 +/- 100 vs. 235 +/- 248, p = 0.002; MWD 297 +/- 273 vs. 474 +/- 359, p = 0.001). Improvement of PWD and MWD could be maintained at follow up (197 +/- 254, p = 0.014; 390 +/- 324, p = 0.035, respectively) with non-smokers showing significantly better sustained PWD and MWD improvement as compared to baseline. Overall, walking capacity correlated with functional status of quality of life. CONCLUSIONS: Major findings of this investigation were that improvement in walking capacity is sustained after completion of supervised exercise training program with best results in patients who quitted or never smoked. Improved walking capacity is associated with increased functional status of quality of life.

Nitric oxide synthase modulates angiogenesis in response to tissue ischemia.

We tested the hypothesis that endothelial nitric oxide synthase (eNOS) modulates angiogenesis in two animal models in which therapeutic angiogenesis has been characterized as a compensatory response to tissue ischemia. We first administered L-arginine, previously shown to augment endogenous production of NO, to normal rabbits with operatively induced hindlimb ischemia. Angiogenesis in the ischemic hindlimb was significantly improved by dietary supplementation with L-arginine, compared to placebo-treated controls; angiographically evident vascularity in the ischemic limb, hemodynamic indices of limb perfusion, capillary density, and vasomotor reactivity in the collateral vessel-dependent ischemic limb were all improved by oral L-arginine supplementation. A murine model of operatively induced hindlimb ischemia was used to investigate the impact of targeted disruption of the gene encoding for ENOS on angiogenesis. Angiogenesis in the ischemic hindlimb was significantly impaired in eNOS-/- mice versus wild-type controls evaluated by either laser Doppler flow analysis or capillary density measurement. Impaired angiogenesis in eNOS-/- mice was not improved by administration of vascular endothelial growth factor (VEGF), suggesting that eNOS acts downstream from VEGF. Thus, (a) eNOS is a downstream mediator for in vivo angiogenesis, and (b) promoting eNOS activity by L-arginine supplementation accelerates in vivo angiogenesis. These findings suggest that defective endothelial NO synthesis may limit angiogenesis in patients with endothelial dysfunction related to atherosclerosis, and that oral L-arginine supplementation constitutes a potential therapeutic strategy for accelerating angiogenesis in patients with advanced vascular obstruction.

Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects.

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.

Bone marrow as a source of endothelial cells for natural and iatrogenic vascular repair.

Postnatal neovascularization has previously been considered synonymous with angiogenesis, but the finding that circulating endothelial progenitor cells (EPCs) may home to sites of neovascularization and there differentiate into endothelial cells (ECs) is consistent with "vasculogenesis," through which the primordial vascular network is established in the embryo. Our findings suggest that growth and development of new blood vessels in the adult are not restricted to angiogenesis but encompass vasculogenesis as well, although the proportional contributions remain to be clarified. Likewise, augmented or retarded neovascularization probably involves enhancement or impariment of the vasculogenesis process.

VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease.

BACKGROUND: Direct transfection of ischemic myocardium with naked plasmid DNA encoding for vascular endothelial growth factor-165 (VEGF165) has been shown to mobilize endothelial progenitor cells (EPCs). This study examined the kinetics of circulating EPCs isolated from peripheral blood mononuclear cells after gene transfer, and their role in neovascularization of ischemic myocardium. METHODS: The mononuclear cell population was isolated from peripheral venous blood samples of patients with functional class III or IV angina receiving intramyocardial VEGF165 gene transfer. Peripheral blood mononuclear cells were examined by an in vitro EPC culture assay and fluorescent-activated cell sorting. The data were compared with a control group consisting of patients who had undergone off-pump coronary artery bypass grafting without receiving gene transfer. RESULTS: Coinciding with a rise in VEGF levels, mobilization of EPCs increased significantly over base line for 9 weeks after the treatment (121+/-14 cells/mm2 versus 36.8+/-8 cells/mm2, p < 0.0005), followed by a subsequent decrease. Fluorescent-activated cell sorting analysis confirmed culture assay data, with a statistically significant rise in cells expressing vascular endothelial-cadherin, CD51/61 [alphavbeta3], CD62E [E-selectin], CD34, and KDR. The control group failed to show significant mobilization of EPCs. CONCLUSIONS: Mobilization of EPCs with resultant postnatal vasculogenesis, may play a role in revascularizing ischemic myocardium following human gene transfer with VEGF165.

Endothelial progenitor cells for regeneration.

Endothelial progenitor cells (EPCs) have been recently isolated from peripheral blood and bone marrow (BM), and shown to be incorporated into sites of physiological and pathological neovascularization in vivo. In contrast to differentiated endothelial cells (ECs), transplantation of EPCs successfully enhanced vascular development by in situ differentiation and proliferation within ischemic organs. Based on such a novel concept of closed up function on EPCs in postnatal neovascularization, the beneficial property of EPC is attractive for cell therapy as well as cell-mediated gene therapy applications targeting regeneration of ischemic tissue.

[Vascular endothelial factor (VEGF): therapeutic angiogenesis and vasculogenesis in the treatment of cardiovascular disease]. / Vaskulärer endothelialer Wachstumsfaktor (VEGF): Therapeutische Angiogenese und Vaskulogenese in der Behandlung kardiovaskulärer Erkrankungen.

The formation of new blood vessel is essential for a variety of physiological processes like embryogenesis and the female reproduction as well as pathological processes like tumor growth, wound healing and neovascularization of ischemic tissue. Vasculogenesis and angiogenesis are the mechanisms responsible for the development of the blood vessels. While angiogenesis refers to the formation of capillaries from pre-existing vessels in the embryo and adult organism, vasculogenesis, the development of new blood vessels from in situ differentiating endothelial cells, has been previously considered restricted to embryogenesis. Recent investigations, however, show the existence of endothelial progenitor cells (EPCs) in the peripheral blood of the adult and their participation in ongoing neovascularization. Molecular and cell-biological experiments suggest that different cytokines and growth factors have a stimulatory effect on these bone-marrow derived EPCs. Results with GM-CSF (granulocyte macrophage-colony stimulating factor) and VEGF (vascular endothelial growth factor) open a new insight into the clinical use of cytokines and in particular the use of growth factors in gene therapy. The administration via protein or plasmid-DNA for neovascularization seems to enhance both pathways, angiogenesis and vasculogenesis.

Gene and stem cell therapy in peripheral arterial occlusive disease.

Peripheral arterial occlusive disease (PAOD) is a manifestation of systemic atherosclerosis strongly associated with a high risk of cardiovascular morbidity and mortality. In a considerable proportion of patients with PAOD, revascularization either by endovascular means or by open surgery combined with best possible risk factor modification does not achieve limb salvage or relief of ischaemic rest pain. As a consequence, novel therapeutic strategies have been developed over the last two decades aiming to promote neovascularization and remodelling of collaterals. Gene and stem cell therapy are the main directions for clinical investigation concepts. For both, preclinical studies have shown promising results using a wide variety of genes encoding for growth factors and populations of adult stem cells, respectively. As a consequence, clinical trials have been performed applying gene and stem cell-based concepts. However, it has become apparent that a straightforward translation into humans is not possible. While several trials reported relief of symptoms and functional improvement, other trials did not confirm this early promise of efficacy. Ongoing clinical trials with an improved study design are needed to confirm the potential that gene and cell therapy may have and to prevent the gaps in our scientific knowledge that will jeopardize the establishment of angiogenic therapy as an additional medical treatment of PAOD. This review summarizes the experimental background and presents the current status of clinical applications and future perspectives of the therapeutic use of gene and cell therapy strategies for PAOD.

Clinical predictors of prophylaxis use prior to the onset of acute venous thromboembolism in hospitalized patients SWIss Venous ThromboEmbolism Registry (SWIVTER).

BACKGROUND: We investigated clinical predictors of appropriate prophylaxis prior to the onset of venous thromboembolism (VTE). METHODS: In 14 Swiss hospitals, 567 consecutive patients (306 medical, 261 surgical) with acute VTE and hospitalization < 30 days prior to the VTE event were enrolled. RESULTS: Prophylaxis was used in 329 (58%) patients within 30 days prior to the VTE event. Among the medical patients, 146 (48%) received prophylaxis, and among the surgical patients, 183 (70%) received prophylaxis (P < 0.001). The indication for prophylaxis was present in 262 (86%) medical patients and in 217 (83%) surgical patients. Among the patients with an indication for prophylaxis, 135 (52%) of the medical patients and 165 (76%) of the surgical patients received prophylaxis (P < 0.001). Admission to the intensive care unit [odds ratio (OR) 3.28, 95% confidence interval (CI) 1.94-5.57], recent surgery (OR 2.28, 95% CI 1.51-3.44), bed rest > 3 days (OR 2.12, 95% CI 1.45-3.09), obesity (OR 2.01, 95% CI 1.03-3.90), prior deep vein thrombosis (OR 1.71, 95% CI 1.31-2.24) and prior pulmonary embolism (OR 1.54, 95% CI 1.05-2.26) were independent predictors of prophylaxis. In contrast, cancer (OR 1.06, 95% CI 0.89-1.25), age (OR 0.99, 95% CI 0.98-1.01), acute heart failure (OR 1.13, 95% CI 0.79-1.63) and acute respiratory failure (OR 1.19, 95% CI 0.89-1.59) were not predictive of prophylaxis. CONCLUSIONS: Although an indication for prophylaxis was present in most patients who suffered acute VTE, almost half did not receive any form of prophylaxis. Future efforts should focus on the improvement of prophylaxis for hospitalized patients, particularly in patients with cancer, acute heart or respiratory failure, and in the elderly.

Stenting of common iliac vein obstructions combined with regional thrombolysis and thrombectomy in acute deep vein thrombosis.

OBJECTIVES: To evaluate the efficacy of stent placement after infrainguinal loco-regional thrombolysis and iliac thrombectomy (surgical TT) of acute deep vein thrombosis (DVT) in patients with May-Thurner-Syndrome. MATERIAL AND METHODS: We retrospectively analysed a group of 11 patients (9 women) (mean age 34 years, range 16-64 years) with surgical TT and additional intra-operative stenting due to compression of the common iliac vein. Patients underwent venography to demonstrate outflow patency after surgical TT, and to identify any obstruction at the level of the left-sided common iliac vein ("Beckenvenen-Sporn"). Obstruction at the level of arterial crossing was treated using Wallstents placed via an introducer sheath from the inguinal access site. Stents were fully deployed using balloons adjusted to the size of vein. Patients were treated with oral anticoagulants for 6 months, and followed using duplex ultrasonography. RESULTS: Technical success defined as complete vein patency and normal valve function was documented in all 11 patients. One patient needed early stent extension due to residual stenosis. At 6 months follow-up one patient (9%) had an asymptomatic occlusion of the stented common iliac vein. In all 11/11 (100%) patients the femoral segment was found to be patent, and in 1/11 (9%) there was mild reflux with few clinical symptoms of post-thrombotic syndrome. The calculated cumulative primary patency rate for venous iliac stents was 82%, and assisted patency rate was 91%, which remained unchanged over a mean follow-up of 22 months. CONCLUSION: Combining surgical TT and stenting of common iliac vein obstructions in DVT is safe, effective, and results in a acceptable venous patency.

[Angiogenesis and vasculogenesis. Therapeutic strategies for stimulation of postnatal neovascularization]. / Angiogenese und Vaskulogenese. Therapeutische Strategien zur Stimulation der postnatalen Neovaskularisation.

The formation of new blood vessel is essential for a variety of physiological processes like embryogenesis and the female reproduction as well as wound healing and neovascularization of ischemic tissue. Major progress in understanding the underlying mechanisms regulating blood vessel growth has offered novel therapeutic options in the treatment of a variety of diseases including ischemic cardiovascular disorders. Vasculogenesis and angiogenesis are the mechanisms responsible for the development of the blood vessels. Angiogenesis refers to the formation of capillaries from preexisting vessels in the embryo and adult organism. While pathologic angiogenesis includes the role of post-natal neovascularization in the pathogenesis of arthritis, diabetic retinopathy, and tumor growth and metastasis, therapeutic angiogenesis, either endogenously or in response to administered growth factors, includes the development of collateral blood vessels in tissue ischemia. Preclinical studies established that angiogenic growth factors could promote collateral artery development in animal models of peripheral and myocardial ischemia. Subsequent clinical trials using gene transfer of naked DNA encoding for VEGF for the treatment of critical limb and myocardial ischemia documented the safety and clinical benefit of this novel therapeutic approach. Several objective methods indicated marked improvement in collateral vessel development. Vasculogenesis describes the development of new blood vessels from in situ differentiating endothelial cells. Recently considered to be restricted to embryogenesis, there exists now striking evidence that endothelial progenitor cells (EPC) circulate also in adult peripheral blood able to participate in ongoing neovascularization. Different cytokines and growth factors have a stimulatory effect on these bone-marrow derived EPC. Granulocyte macrophage colony stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF) mobilize EPC from the bone marrow into the peripheral circulation. While their endogenous contribution to postnatal neovascularization needs to be documented, the iatrogenic expansion and mobilization of EPC might represent an effective means to augment the resident population of endothelial cells (ECs). This kind of cell therapy for tissue regeneration in ischemic cardiovascular diseases opens a novel and challenging clinical option besides or in addition to the use of growth factors in gene therapy.

Stem cell therapy and gene transfer for regeneration.

The committed stem and progenitor cells have been recently isolated from various adult tissues, including hematopoietic stem cell, neural stem cell, mesenchymal stem cell and endothelial progenitor cell. These adult stem cells have several advantages as compared with embryonic stem cells as their practical therapeutic application for tissue regeneration. In this review, we discuss the promising gene therapy application of adult stem and progenitor cells in terms of modifying stem cell potency, altering organ property, accelerating regeneration and forming expressional organization.

Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization.

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.