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BACKGROUND In patients with knee osteoarthritis (KOA), the descending genicular artery (DGA) showed abnormal angiogenesis. However, the non-invasive assessment method of DGA remains unclear. The aim of this study was to clarify the characteristics of blood flow velocity of the DGA in patients with KOA and to examine the factors involved in the changes. METHODS The KOA group included 22 knees of 22 patients with KOA (4 males, 18 females; mean age, 72.3 ± 7.5 years) and the control group included 22 knees (4 males, 18 females; mean age, 71.3 ± 5.4 years) of 22 healthy adults. The peak systolic blood flow velocity (PSV) in each group was measured using ultrasonography. The KOA group was classified into the effusion group and the non-effusion group based on observed effusion, and the PSV was compared between the two groups. The relationships between PSV and suprapatellar bursa intracavitary distance, pain, femorotibial angle, Japanese Knee Osteoarthritis Measure were also investigated. RESULTS The PSV in the KOA group (51.5 ± 12.9 cm/s) was significantly higher than that in the control group (29.3 ± 4.4 cm/s) (P

PURPOSE To evaluate the safety and 2-year follow-up clinical outcomes of transcatheter arterial embolization (TAE) using imipenem/cilastatin sodium for chronic low back pain resistant to conservative treatment. MATERIALS AND METHODS A retrospective review identified 14 patients who underwent TAE for chronic low back pain between October 2017 and August 2018. Patients with low back pain related to the facet or sacroiliac joint, lasting ≥ 6 months, refractory to ≥ 3 months of conservative treatment were eligible for TAE. Each patient received embolization of feeding arteries of painful regions. The changes in brief pain inventory (BPI) scores, adverse events, and the Oswestry Disability Index (ODI) were evaluated at baseline and 1, 3, and 24 months after TAE. Clinical success was defined as BPI maximum pain intensity decrease of ≥ 2 and ODI decrease of ≥ 10 points from baseline. RESULTS Follow-up data were available in 13 and 11 patients, at 3 and 24 months after embolization, respectively. Intention-to-treat clinical success was obtained in 11/14 (79%) of patients at 3 months and 8/14 (57%) of patients at 24 months after TAE. Mean BPI maximum pain intensity and ODI scores decreased significantly from baseline to 1, 3, and 24 months after treatment (7.6 vs.. 4.3, 3.4, and 4.1; 40.8 vs 21.5, 20.0, and 23.8, respectively; all P

PURPOSE To evaluate the efficacy and safety of intra-arterial infusion of temporary embolic material with/without radiographic monitoring via a needle placed into the radial artery to occlude abnormal neovessels for trapeziometacarpal osteoarthritis. MATERIALS AND METHODS Thirty-one patients having Eaton stage II or III osteoarthritis, with a symptom duration longer than 6 months, resistant to conservative therapy for at least 3 months were prospectively enrolled. All procedures were performed by infusing imipenem/cilastatin sodium through a 24-gauge needle that was percutaneously inserted into the radial artery. Seven patients underwent the procedure with fluoroscopy, and 21 patients underwent the procedure without fluoroscopy. The mean Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, numerical rating scale (NRS), and Patient Global Impression of Change (PGIC) scale were evaluated before and at 2, 6, and 24 months after the first procedure. RESULTS Technical success was 100%. The mean procedure time (from the beginning of local anesthesia to the removal of needle) was 2.9 minutes ± 1.6. The QuickDASH score improved from the baseline to 2, 6, and 24 months (49.2 ± 11.2 vs 22.1 ± 11.2, 20.9 ± 16.6, and 19.5 ± 16.1, respectively, all P

Genicular artery embolization (GAE) is a minimally invasive outpatient therapy for osteoarthritis (OA) related knee pain, refractory to conservative management. This intervention targets neovasculature which arises in the setting of angiogenesis in OA. Various clinical trials highlighted in this manuscript suggest that GAE is effective in durably reducing OA-related knee pain, with a limited adverse event profile. This review also explores the clinical evaluation of GAE candidates, genicular artery anatomy, technical components of the procedure, and imaging from various GAE embolizations. It also discusses future directions for research which may illuminate predictors of clinical success as well as avenues for evolution in the GAE treatment.

This case report concerns a 51-year-old woman with a 6-month history of severe right heel pain diagnosed as plantar fasciitis (PF) treated with intra-arterial infusion of imipenem/cilastatin (IPM/CS) through a 24G indwelling needle directly inserted into the posterior tibial artery (PTA). Angiography of the indwelling needle immediately before the infusion of IPM/CS demonstrated an increased number of abnormal vessels at the calcaneal attachment of the plantar fascia. Two procedures were planned: The first procedure was performed, and the second was performed 1 month after the first. A week after the first treatment, her pain gradually decreased. Three months after the first treatment, she no longer had difficulties with activities of daily living. Intra-arterial infusion of IPM/CS directly through an indwelling needle into the PTA represents a minimally invasive embolic treatment option for PF.

Purpose: To explore the association between baseline osteoarthritis (OA)-related magnetic resonance (MR) imaging features and pain reduction after genicular artery embolization (GAE) in patients with mild-to-moderate symptomatic knee OA resistant to conservative therapy. Materials and Methods: This was a retrospective analysis of patients with mild-to-moderate symptomatic knee OA treated with GAE using imipenem-cilastatin sodium. The clinical outcome was scored at baseline and 6 months after treatment using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). MR images were scored using the MR imaging osteoarthritis knee score. Linear regression was used to evaluate associations of before-treatment MR imaging scores with WOMACpain and WOMACtotal reduction after 6 months. Results: Fifty-four patients (22.2% male; median age, 69.4 years; median WOMACpain at baseline, 12) were evaluated. Of all OA features scored, a higher cartilage full-thickness defect score showed the strongest association with less reduction of both WOMACpain (B,−0.63 [95% confidence interval (CI), −0.91 to −0.34]; P total scores (B, −1.77 [95% CI, −2.87 to −0.67]; P pain reduction (all P

Frozen shoulder (FS) is speculated to have an inflammatory etiology. On angiography, abnormal angiogenesis is observed around the affected shoulder, suggesting a possible source of inflammation and pain. The effectiveness and safety of transarterial embolization (TAE) targeting abnormally proliferating blood vessels have been reported. This study investigated changes in chronic inflammatory and hypoxic status before and after TAE in FS by [Fifteen patients with unilateral FS, persistent for more than 6 months, who were refractory to conservative treatments, underwent TAE using the temporary embolic agent imipenem/cilastatin. Patients underwent PET/CT with FDG (as a biomarker of inflammation) before and 8 weeks after TAE. Regional uptake was evaluated by the maximum standardized uptake value (SUVmax). The lesion-side to (contralateral-) normal-side uptake ratio (L/C ratio) was also calculated. Pain and functional scales, range-of-motion, and laboratory tests, including WBC, CRP, IL-6, VEGF, and TNFα were evaluated.On FDG-PET, the average SUVmax of the lesion-side was significantly greater than that of the normal-side (SUVmax before TAE: 3.11 ± 1.25 vs. 1.95 ± 1.15, p = 0.0001; 8-weeks post-TAE: 2.36 ± 0.74 vs. 1.78 ± 0.69, p = 0.0002). The mean L/C ratios before TAE (1.71 ± 0.60) decreased after TAE (1.37 ± 0.29, p = 0.011). The decrease of FDG uptake (-21.1 ± 12.2%) showed a significant correlation with the change in the pain scale score (r = -0.56, p = 0.039) and extension score (r = -0.59, p = 0.026).Chronic inflammation in FS, as demonstrated by FDG uptake, was decreased after TAE. Thus, chronic inflammation is likely to be an underlying mechanism that should be targeted for symptomatic improvement of frozen shoulder.

To assess the feasibility of transarterial embolization (TAE) for recalcitrant nighttime shoulder pain in a multicentric study.This prospective, open-label, feasibility trial included 100 patients treated at 5 institutions. TAE was performed in 76 patients with adhesive capsulitis (AC) and 24 patients with symptomatic rotator cuff tears (sRCTs). The ipsilateral radial artery was punctured, and imipenem/cilastatin sodium was infused as an embolic agent. Adverse events, 10 point pain numerical rating scale (NRS), range of motion (ROM) of the shoulder joint, and quality of life (via the EuroQol-5D [EQ-5D]) were evaluated.All patients exhibited neovascularity on baseline angiography, and all TAE procedures were performed successfully. No patient experienced a major adverse event. The mean nighttime pain NRS scores at baseline and 1, 3, and 6 months after TAE were 6.4 ± 2.2, 3.4 ± 2.6, 2.3 ± 2.5, and 1.6 ± 2.2, respectively (for all, P.001). The mean ROM of anterior elevation at baseline and 1, 3, and 6 months after TAE were 97° ± 29°, 119° ± 28°, 135° ± 27°, and 151° ± 17°, respectively (for all, P.001). The mean EQ-5D scores at baseline and 1, 3, and 6 months after TAE were 0.63 ± 0.17, 0.73 ± 0.16, 0.80 ± 0.17, and 0.84 ± 0.17, respectively (for all, P.001). There was no significant difference in the clinical success rate between the AC and sRCT groups.TAE for nighttime shoulder pain caused by AC and sRCTs was feasible with sufficient safety and efficacy.

In recent years, transcatheter arterial embolization (TAE) using imipenem/cilastatin (IPM/CS) has attracted attention as a treatment for relieving osteoarthritis (OA) pain. However, IPM/CS is not approved by Japanese medical insurance for use as an embolic material. Therefore, it is necessary to develop new embolic materials for TAE to relieve OA pain. The purpose of this study was to develop a swine model of knee arthritis and embolize abnormal neovessels (ANs) using two different embolic materials. We compared the embolic effects and tissue damage in knees.Knee arthritis was induced by intra-articular injection of papain into 12 knees in six female swine. The swine were divided into two groups of three swine each (six knees per group) for embolization of ANs in the knees with either IPM/CS or soluble gelatin sponge particles (SGSs). Three days after embolization, we compared the embolic effects using angiography and the tissue damage histopathologically.ANs were observed in all 12 knees at 42 days after papain injection. The ANs disappeared and the patent arteries were recanalized 3 days after TAE in all 12 knees. Histopathological evaluation revealed synovitis changes, such as synovial thickening and inflammatory cell infiltration, in all 12 knees. There was no evidence of skin or muscle necrosis in either group. The appearance of ANs, recanalization of the parent arteries, and histopathological outcomes were not significantly different between the two groups.SGSs were as safe as IPM/CS for TAE of ANs in this swine model of knee arthritis.

To evaluate the safety and efficacy of transcatheter arterial microembolization for patients with trapezius myalgia. We retrospectively evaluated the prospectively collected data of patients with trapezius myalgia for > 6 months who were refractory to conservative treatment and were treated by transcatheter arterial microembolization between October 2017 and January 2019. Transcatheter arterial microembolization was performed using imipenem/cilastatin on the vessels of the transverse cervical artery, suprascapular artery, and circumflex scapular artery according to the region of pain. Forty-two patients were treated by transcatheter arterial microembolization and followed up for 6 months. No major adverse events occurred related to the procedures. The brief pain inventory worst pain scores significantly improved at 1, 2, 3, and 6 months after transcatheter arterial microembolization (8.6 ± 1.3 (before procedure) vs. 5.1 ± 2.9, 4.4 ± 2.9, 4.1 ± 2.8, and 3.9 ± 2.9, respectively, P

Primary Spontaneous osteonecrosis of the knee (SPONK) was a result of a subchondral insufficiency fracture based on histopathological examinations. There were few studies examining patients who underwent unicompartmental knee arthroplasty (UKA) for the treatment of primary SPONK. The aim of this study was to investigate (1) patient-reported outcome measure (PROM), (2) survivorship of revision as end point and (3) survivorship of complication as end point in patients with primary SPONK. The clinical examinations of a consecutive series of 61 medial UKAs for primary SPONK of the medial femoral condyle from 2008 to 2012 were evaluated retrospectively at our institution. There were 18 males and 43 females with a mean age of 73.7 years (60–91). In all patients, preoperative radiographs were analyzed according to the stage of primary SPONK. We conducted Kaplan–Meier survival analyses using revision and complications for any reasons as the end point. Mean follow-up was 6.6 years (range 6–10). UKA using Physica ZUK (LIMA Corporate. UD, Italy) for SPONK improved patients’ 2011 Knee Society symptom score, patient satisfaction, patient activities, EQ-5D and postoperative ranges of motion compared with their preoperative status (P

PURPOSE To evaluate if synovial inflammation and hypervascularization are present in a dog model of knee osteoarthritis and can be detected on conventional magnetic resonance imaging (MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), contrast-enhanced magnetic resonance imaging (CE-MRI), and quantitative digital subtraction angiography (Q-DSA) imaging. MATERIALS AND METHODS Six dogs underwent MRI and angiography of both knees before and 12 weeks after right knee anterior cruciate ligament injury. Synovial vascularity was evaluated on CE-MRI, DCE-MRI, and Q-DSA by 2 independent observers. Synovial inflammation and vascularity were histologically scored independently. Cartilage lesions and osteophytes were analyzed macroscopically, and cartilage volumetry was analyzed by MRI. Vascularity and osteoarthritis markers on imaging were compared before and after osteoarthritis generation, and between the osteoarthritis model and the control knee, using linear mixed models accounting for within-dog correlation. RESULTS In all knees, baseline imaging showed no abnormalities. Control knees did not develop significant osteoarthritis changes, synovial inflammation, or hypervascularization. In osteoarthritis knees, mean synovial enhancement score on CE-MR imaging increased by 13.1 ± 0.59 (P < .0001); mean synovial inflammation variable increased from 47.33 ± 18.61 to 407.97 ± 18.61 on DCE-MR imaging (P < .0001); and area under the curve on Q-DSA increased by 1058.58 ± 199.08 (P = .0043). Synovial inflammation, hypervascularization, and osteophyte formations were present in all osteoarthritis knees. Histology scores showed strong correlation with CE-MR imaging findings (Spearman correlation coefficient [SCC] = 0.742; P = .0002) and Q-DSA findings (SCC = 0.763; P < .0001) and weak correlation with DCE-MR imaging (SCC = -0.345; P = .329). Moderate correlation was found between CE-MR imaging and DSA findings (SCC = 0.536; P = .0004). CONCLUSIONS In this early-stage knee osteoarthritis dog model, synovial inflammation and hypervascularization were found on imaging and confirmed by histology.

Phantom limb pain is a frequent consequence of the amputation; currently available treatments are far from satisfactory. The present report describes a case in which transcatheter arterial microembolization had a remarkable curative effect on phantom limb pain persisting for 17 years. The patient began feeling phantom limb sensations and brief intermittent pain following lower limb amputation above the knee in 2001. The frequency, intensity, and duration of the pain increased over time, and it was resistant to conservative treatments. Following transcatheter arterial microembolization in 2018, patient immediately experienced marked improvement. The pain has been infrequent, much less intense, and did not interfere with daily life 6 months posttreatment. Transcatheter arterial microembolization could be an alternative treatment option for phantom limb pain. LEVEL OF EVIDENCE: IV, Case Report.

Osteoarthritis is a common cause of pain and disability. Mild to moderate knee osteoarthritis that is resistant to nonsurgical options and not severe enough to warrant joint replacement represents a challenge in its management. On the basis of the hypothesis that neovessels and accompanying nerves are possible sources of pain, previous work demonstrated that transcatheter arterial embolization for chronic painful conditions resulted in excellent pain relief. We hypothesized that transcatheter arterial embolization can relieve pain associated with knee osteoarthritis.Transcatheter arterial embolization for mild to moderate knee osteoarthritis using imipenem/cilastatin sodium or 75 μm calibrated Embozene microspheres as an embolic agent has been performed in 11 and three patients, respectively. We assessed adverse events and changes in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) scores.Abnormal neovessels were identified within soft tissue surrounding knee joint in all cases by arteriography. No major adverse events were related to the procedures. Transcatheter arterial embolization rapidly improved WOMAC pain scores from 12.2 ± 1.9 to 3.3 ± 2.1 at 1 month after the procedure, with further improvement at 4 months (1.7 ± 2.2) and WOMAC total scores from 47.3 ± 5.8 to 11.6 ± 5.4 at 1 month, and to 6.3 ± 6.0 at 4 months. These improvements were maintained in most cases at the final follow-up examination at a mean of 12 ± 5 months (range 4-19 months).Transcatheter arterial embolization for mild to moderate knee osteoarthritis was feasible, rapidly relieved resistant pain, and restored knee function.

Abnormal vessels and accompanying nerves are possible sources of pain with lateral epicondylitis. The purpose of this study was to describe the safety and efficacy of transcatheter arterial embolization (TAE) for lateral epicondylitis resistant to conservative treatment.This prospective study was conducted in 24 patients with lateral epicondylitis resistant to conservative treatments for more than 3 months, with a symptom duration longer than 6 months, and with moderate to severe pain who were treated with TAE between March 2013 and October 2014. Two patients were lost to follow-up, and the remaining 22 patients were followed up for 2 years after TAE.Abnormal vessels were identified in all of the patients. No major adverse events were observed. The Quick Disabilities of the Arm, Shoulder and Hand scores at baseline significantly decreased at 1, 3, 6, and 24 months after treatment (50.8 vs 23.4, 8.3, 5.3, and 2.7, respectively; all P .001). There was a statistically significant (P .001) change from baseline to the last observed value in all of the clinical parameters, including visual analog scale pain score, Patient-Rated Tennis Elbow Evaluation score, and pain-free grip strength. Magnetic resonance images obtained 2 years after TAE showed an improvement in tendinosis and tear scores compared with baseline, and no patients showed bone marrow necrosis, obvious cartilage loss, or muscle atrophy.TAE could be one possible treatment option for patients with lateral epicondylitis that fails to improve with conservative treatments.

To describe the safety and efficacy of transcatheter arterial embolization for mild to moderate radiographic knee osteoarthritis (OA) that is resistant to conservative treatment.This prospective study included 72 patients (95 knees) with OA of Kellgren-Lawrence (KL) grade 1-3 and persisting moderate to severe pain that was resistant to conservative management who were treated with transcatheter arterial embolization between July 2012 and March 2016. Clinical outcomes were evaluated at 1, 4, and 6 months and then every 6 months for a maximum of 4 years. The Whole-Organ Magnetic Resonance Imaging Score (WORMS) was evaluated at baseline and at 2 years after embolization in 35 knees.Abnormal neovessels were identified in all cases. There were no major adverse events related to the procedures. Mean Western Ontario and McMaster Universities Osteoarthritis Index pain scores significantly decreased from baseline to 1, 4, 6, 12, and 24 months after treatment (12.1 vs 6.2, 4.4, 3.7, 3.0, and 2.6; all P.001). The cumulative clinical success rates at 6 months and 3 years after embolization were 86.3% (95% confidence interval [CI], 78%-92%) and 79.8% (95% CI, 69%-87%), respectively. WORMS scores at 2 years after embolization in 35 knees showed significant improvement of synovitis vs baseline (P = .0016) and no osteonecrosis or other evidence indicating aggressive progression of degenerative changes.Transcatheter arterial embolization significantly improved pain symptoms and clinical function in patients with mild to moderate knee OA that was resistant to conservative treatment.

The vascular and nervous systems display a high degree of cross-talk and depend on each other functionally. In the vascularization of the central nervous system, astrocytes have been thought to sense tissue oxygen levels in hypoxia-inducible factors (HIFs)-dependent manner and control the vascular growth into the hypoxic area by secreting VEGF. However, recent genetic evidences demonstrate that not only astrocyte HIFs but also astrocyte VEGF expression is dispensable for developmental angiogenesis of the retina. This study demonstrates that hypoxia-inducible factor 1 alpha subunit (HIF-1α), a key transcription factor involved in cellular responses to hypoxia, is most abundantly expressed in the neuroretina, especially retinal progenitor cells (RPCs). A neuroretina-specific knockout of HIF-1α (αCre(+)Hif1α(flox/flox)) showed impaired vascular development characterized by decreased tip cell filopodia and reduced vessel branching. The astrocyte network was hypoplastic in αCre(+)Hif1α(flox/flox) mice. Mechanistically, platelet-derived growth factor A (PDGF-A), a mitogen for astrocytes, was downregulated in the neuroretina of αCre(+)Hif1α(flox/flox) mice. Supplementing PDGF-A restored reduced astrocytic and vascular density in αCre(+)Hif1α(flox/flox) mice. Our data demonstrates that the neuroretina but not astrocytes acts as a primary oxygen sensor which ultimately controls the retinal vascular development by regulating an angiogenic astrocyte template.

Bone marrow-derived cells (BMDCs) contribute to postnatal vascular growth by differentiating into endothelial cells or secreting angiogenic factors. However, the extent of their endothelial differentiation highly varies according to the angiogenic models used. Wound healing is an intricate process in which the skin repairs itself after injury. As a process also observed in cancer progression, neoangiogenesis into wound tissues is profoundly involved in this healing process, suggesting the contribution of BMDCs. However, the extent of the differentiation of BMDCs to endothelial cells in wound healing is unclear. In this study, using the green fluorescent protein-bone marrow chim-eric experiment and high resolution confocal microscopy at a single cell level, we observed no endothelial differentiation of BMDCs in 2 acute wound healing models (dorsal excisional wound and ear punch) and a chronic wound healing model (decubitus ulcer). Instead, a major proportion of BMDCs were macrophages. Indeed, colony-stimulating factor 1 (CSF-1) inhibition depleted approximately 80% of the BMDCs at the wound healing site. CSF-1–mutant (CSF-1op/op) mice showed significantly reduced neoangiogenesis into the wound site, supporting the substantial role of BMDCs as macrophages. Our data show that the proangiogenic effects of macrophages, but not the endothelial differentiation, are the major contribution of BMDCs in wound healing.

To evaluate clinical outcomes of transcatheter arterial embolization (TAE) for adhesive capsulitis resistant to conservative treatments.This study comprised 25 patients (18 women and 7 men; mean age, 53.8 y; range, 39-68 y) with adhesive capsulitis resistant to conservative treatments. TAE was performed, and adverse events (AEs), pain visual analog scale (VAS) score changes, range of motion (ROM), and American Shoulder and Elbow Surgeons (ASES) scores were assessed.Abnormal vessels were identified in all patients. No major AEs were associated with TAE. One patient was lost to follow-up. The remaining 24 patients were available for final follow-up (mean, 36.1 months; range, 30-44 months). Of the 24 patients, 16 (67%) experienced quick improvement of nighttime pain (ie, VAS scores decreased50% from baseline) within 1 week, and 21 (87%) improved within 1 month. In terms of mean overall pain (ie, pain at its worst), VAS scores significantly decreased at 1, 3, and 6 months after treatment (82 mm before treatment vs 52, 19, and 8 mm after treatment; P.001). ASES scores significantly improved at 1, 3, and 6 months after treatment (16.1 before treatment vs 41.4, 69.1, and 83.5 after treatment; P.001). No symptom recurrence or late-onset AEs were observed. Shoulder ROM and function further improved during midterm follow-up.TAE is a possible treatment option for patients with adhesive capsulitis that has failed to improve with conservative treatments.

Background: Neovessels and accompanying nerves are possible sources of pain. We postulated that transcatheter arterial embolization of abnormal neovessels would relieve pain and symptoms in patients with adhesive capsulitis. Methods: Adhesive capsulitis was treated by transcatheter arterial embolization in 7 patients. Adverse events, changes in visual analog scale scores for night pain and overall shoulder pain, and changes in range of motion and American Shoulder and Elbow Surgeons scores were assessed at 1 week and at 1, 3, and 6 months after the procedure. Results: Abnormal neovessels were identified at the rotator interval in all patients. No major or minor adverse events were associated with the procedures. Transcatheter arterial embolization rapidly decreased nighttime pain scores from 67 � 14 mm to 27 � 14 mm at 1 week after the procedure, with further improvement at 1 and 6 months (6 � 8 mm and 2 � 5 mm, respectively). The American Shoulder and Elbow Surgeons score significantly improved from 17.8 � 4.5 to 39.8 � 12.0, 64.3 � 13.9, and 76.2 � 4.4 at 1, 3, and 6 months, respectively. Conclusion: All patients with adhesive capsulitis had abnormal neovessels at the rotator interval. Transcatheter arterial embolization was feasible, relieved unrelenting pain, and restored shoulder function. Level of evidence: Level IV, Case Series, Treatment Study. 2014 Journal of Shoulder and Elbow Surgery Board of Trustees.

Purpose: To evaluate the feasibility and effects of transcatheter arterial embolization with imipenem/cilastatin sodium (CS) to treat tendinopathy and enthesopathy that are refractory to traditional nonsurgical management. Materials and Methods: Transcatheter arterial embolization with imipenem/CS as an embolic agent was performed in seven patients (five men; mean age, 51.7 y) with tendinopathy and enthesopathy (patellar tendinopathy, n ¼ 1; rotator cuff tendinopathy, n ¼ 2; plantar fasciitis, n ¼ 1; lateral epicondylitis, n ¼ 1; iliotibial band syndrome, n ¼ 1; and Achilles insertion tendinopathy, n ¼ 1). All patients had unrelenting pain at the site of tendinopathy and enthesopathy before the procedure. Technical success, adverse events, and changes in visual analog scale (VAS) scores were assessed. Results: All procedures were technically successful, and no major adverse events developed. Compared with before the procedure, mean VAS scores were significantly decreased at 1 day, 1 week, and 1 and 4 months after the procedure (72.7 mm 9.9 vs 17.4 mm 18.5, 16.0 mm 18.1, 13.7 mm 7.3, and 9.7 mm 6.8, respectively; all P o .001). Conclusions: Transcatheter arterial embolization with imipenem/CS was feasible and effectively relieved unrelenting pain associated with tendinopathy and enthesopathy.

The BM microenvironment is required for the maintenance, proliferation, and mobilization of hematopoietic stem and progenitor cells (HSPCs), both during steady-state conditions and hematopoietic recovery after myeloablation. The ECM meshwork has long been recognized as a major anatomical component of the BM microenvironment; however, the molecular signatures and functions of the ECM to support HSPCs are poorly understood. Of the many ECM proteins, the expression of tenascin-C (TN-C) was found to be dramatically up-regulated during hematopoietic recovery after myeloablation. The TN-C gene was predominantly expressed in stromal cells and endothelial cells, known as BM niche cells, supporting the function of HSPCs. Mice lacking TN-C (TN-C−/−) mice showed normal steady-state hematopoiesis; however, they failed to reconstitute hematopoiesis after BM ablation and showed high lethality. The capacity to support transplanted wild-type hematopoietic cells to regenerate hematopoiesis was reduced in TN-C−/− recipient mice. In vitro culture on a TN-C substratum promoted the proliferation of HSPCs in an integrin α9–dependent manner and up-regulated the expression of the cyclins (cyclinD1 and cyclinE1) and down-regulated the expression of the cyclin-dependent kinase inhibitors (p57Kip2, p21Cip1, p16Ink4a). These results identify TN-C as a critical component of the BM microenvironment that is required for hematopoietic regeneration.

The ataxia telangiectasia mutated (ATM) kinase, a master regulator of the DNA damage response (DDR), acts as a barrier to cellular senescence and tumorigenesis. Aside from DDR signaling, ATM also functions in oxidative defense. Here we show that Atm in mice is activated specifically in immature vessels in response to the accumulation of reactive oxygen species (ROS). Global or endothelial-specific Atm deficiency in mice blocked pathological neoangiogenesis in the retina. This block resulted from increased amounts of ROS and excessive activation of the mitogen activated kinase p38α rather than from defects in the canonical DDR pathway. Atm deficiency also lowered tumor angiogenesis and enhanced the antiangiogenic action of vascular endothelial growth factor (Vegf) blockade. These data suggest that pathological neoangiogenesis requires ATM-mediated oxidative defense and that agents that promote excessive ROS generation may have beneficial effects in the treatment of neovascular disease.

Newly identified tissue-resident vascular precursor cells are recruited into growing vessels and contribute to vasculogenesis in adult mice., Vasculogenesis describes the process of de novo vessel formation from vascular precursor cells. Although formation of the first major vessels, such as the dorsal aorta and cardinal veins, occurs during embryonic vasculogenesis, the contribution of precursor cell populations to postnatal vessel development is not well understood. Here, we identified a novel population of postnatal vascular precursor cells in mice. These cells express the Schwann cell protein myelin protein zero (Po) and exhibit a CD45−CD31−VEcad−c-kit+CXCR4+ surface phenotype. Po+ vascular precursors (PVPs) are recruited into the growing vasculature, and comprise a minor population of arterial endothelial cells in adult mice. Recruitment of PVPs into growing vessels is mediated by CXCL12–CXCR4 signaling, and is enhanced during vascular expansion induced by Notch inhibition. Po-specific ablation of Flk1, a receptor for VEGF, results in branching defects and insufficient arterial patterning in the retina, as well as reduced neovascularization of tumors and ischemic tissues. Thus, in postnatal mice, although growing vessels are formed primarily by angiogenesis from preexisting vessels, a minor population of arterial endothelia may be derived from tissue-resident vascular precursor cells.