Yuji Okuno

Pathological neoangiogenesis depends on oxidative stress regulation by ATM

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.

Extracellular matrix protein tenascin-C is required in the bone marrow microenvironment primed for hematopoietic regeneration

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 (p57(Kip2), p21(Cip1), p16(Ink4a)). These results identify TN-C as a critical component of the BM microenvironment that is required for hematopoietic regeneration.

Bone marrow-derived cells serve as proangiogenic macrophages but not endothelial cells in wound healing

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-1(op/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.

The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner

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.

Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero

Newly identified tissue-resident vascular precursor cells are recruited into growing vessels and contribute to vasculogenesis in adult mice.

Short-term results of transcatheter arterial embolization for abnormal neovessels in patients with adhesive capsulitis: a pilot study

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.

Transcatheter Arterial Embolization Using Imipenem/Cilastatin Sodium for Tendinopathy and Enthesopathy Refractory to Nonsurgical Management

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 = 1; rotator cuff tendinopathy, n = 2; plantar fasciitis, n = 1; lateral epicondylitis, n = 1; iliotibial band syndrome, n = 1; and Achilles insertion tendinopathy, n = 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< .001). CONCLUSIONS Transcatheter arterial embolization with imipenem/CS was feasible and effectively relieved unrelenting pain associated with tendinopathy and enthesopathy.

Clinical Outcomes of Transcatheter Arterial Embolization for Adhesive Capsulitis Resistant to Conservative Treatment

PURPOSE To evaluate clinical outcomes of transcatheter arterial embolization (TAE) for adhesive capsulitis resistant to conservative treatments. MATERIALS AND METHODS 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. RESULTS 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 decreased > 50% 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. CONCLUSIONS TAE is a possible treatment option for patients with adhesive capsulitis that has failed to improve with conservative treatments.

Transcatheter arterial embolization of abnormal vessels as a treatment for lateral epicondylitis refractory to conservative treatment: a pilot study with a 2-year follow-up

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION TAE could be one possible treatment option for patients with lateral epicondylitis that fails to improve with conservative treatments.