Nerve growth factor stimulates regeneration of perivascular nerve, and induces the maturation of microvessels around the injured artery.

An immature vasa vasorum in the adventitia of arteries has been implicated in induction of the formation of unstable atherosclerotic plaques. Normalization/maturation of the vasa vasorum may be an attractive therapeutic approach for arteriosclerotic diseases. Nerve growth factor (NGF) is a pleotropic molecule with angiogenic activity in addition to neural growth effects. However, whether NGF affects the formation of microvessels in addition to innervation during pathological angiogenesis is unclear. In the present study, we show a new role for NGF in neovessels around injured arterial walls using a novel in vivo angiogenesis assay. The vasa vasorum around arterial walls was induced to grow using wire-mediated mouse femoral arterial injury. When collagen-coated tube (CCT) was placed beside the injured artery for 7-14 days, microvessels grew two-dimensionally in a thin layer on the CCT (CCT-membrane) in accordance with the development of the vasa vasorum. The perivascular nerve was found at not only arterioles but also capillaries in the CCT-membrane. Biodegradable hydrogels containing VEGF and NGF were applied around the injured artery/CCT. VEGF significantly increased the total length and instability of microvessels within the CCT-membrane. In contrast, NGF induced regeneration of the peripheral nerve around the microvessels and induced the maturation and stabilization of microvessels. In an ex vivo nerve-free angiogenesis assay, although NGF potentially stimulated vascular sprouting from aorta tissues, no effects of NGF on vascular maturation were observed. These data demonstrated that NGF had potent angiogenic effects on the microvessels around the injured artery, and especially induced the maturation/stabilization of microvessels in accordance with the regeneration of perivascular nerves.

Apurinic/apyrimidinic endonucelase 1 maintains adhesion of endothelial progenitor cells and reduces neointima formation.

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that processes DNA-repair function and controls cellular response to oxidative stress. Endothelial progenitor cells (EPCs) are recruited to oxidative stress-rich injured vascular walls and positively contribute to vascular repair and endothelialization. We hypothesized that APE1 functions for EPCs-mediated inhibition of neointima formation in injured vasculature. EPCs isolated from bone marrow cells of C57BL6 mice (12-16 wk old) were able to survive in the presence of hydrogen peroxide (H2O2; up to 1,000 µM) due to the highly expressed reactive oxygen species (ROS) scavengers. However, adhesion capacity of EPCs was significantly inhibited by H2O2 (100 µM) even though an intracellular ROS was retained at small level. An APE1-selective inhibitor or RNA interference-mediated knockdown of endogenous APE1 in EPCs aggravated the H2O2-mediated inhibition of EPCs-adhesion. In contrast, when APE1 was overexpressed in EPCs using an adenovirus harboring the APE1 gene (APE-EPCs), adhesion was significantly improved during oxidative stress. To examine in vivo effects of APE1 in EPCs, APE-EPCs were transplanted via the tail vein after wire-mediated injury of the mouse femoral artery. The number of adherent EPCs at injured vascular walls and the vascular repair effect of EPCs were enhanced in APE-EPCs compared with control EPCs. Among the cellular functions of EPCs, adhesion is especially sensitive to oxidative stress. APE1 enhances in vivo vascular repair effects of EPCs in part through the maintenance of adhesion properties of EPCs. APE1 may be a novel and useful target gene for effective cellular transplantation therapy.

Impaired ventricular repolarization dynamics in patients with early repolarization syndrome.

INTRODUCTION: Almost all current investigations on early repolarization syndrome (ERS) have focused on the J-wave characteristics and ST-segment configuration; however, few have reported on ventricular repolarization indexes in ERS. METHODS AND RESULTS: A total of 145 subjects were enrolled: 10 ERS patients, 45 uneventful ER pattern (ERP) subjects, and 90 healthy controls without J waves or ST-segment elevation. Ambulatory ECG-derived parameters (QT, QTc(B), QTc(F), T peak-Tend(Tpe), and QT/RR slope) were measured and statistically compared. Among the groups, there was no significant difference in the average QT and QTc(B); however, ERS patients had the shortest QTc(F) and longest Tpe (QTc(F): 396.2 ± 19 vs 410.4 ± 20 vs 419.2 ± 19 milliseconds, P = 0.036, Tpe: 84.9 ± 12 vs 70.4 ± 11 vs 66.9 ± 15 milliseconds, P < 0.001, for the ERS, ERP, and control groups, respectively). Importantly, the 24-hour QT/RR slope was significantly smaller in the ERS than ERP and control groups (QT/RR: 0.105 ± 0.01 vs 0.154 ± 0.02 vs 0.161 ± 0.03, respectively; P < 0.001). When analyzing the diurnal and nocturnal QT/RR slopes, ERS patients had small diurnal and nocturnal QT/RR slopes while the ERP and control groups had large diurnal and small nocturnal QT/RR slopes (diurnal QT/RR: 0. 077 ± 0.01 vs 0.132 ± 0.03 vs 0.143 ± 0.03, P < 0.001; nocturnal QT/RR: 0.093 ± 0.02 vs 0.129 ± 0.03 vs 0.130 ± 0.04, P = 0.02 in the ERS, ERP, and control groups, respectively). CONCLUSION: ERS patients had a continuously depressed diurnal and nocturnal adaptation of the QT interval to the heart rate. Such abnormal repolarization dynamics might provide a substrate for reentry and be an important element for developing ventricular fibrillation in the ERS cohort.

Prostacyclin stimulated integrin-dependent angiogenic effects of endothelial progenitor cells and mediated potent circulation recovery in ischemic hind limb model.

BACKGROUND: Prostacyclin (PGI2) enhances angiogenesis, especially in cooperation with bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the mechanisms of PGI2 in EPC-mediated angiogenesis in vivo remain unclear. The purpose of this study was to clarify the role of PGI2 in EPC-mediated angiogenesis using BM-specific IP deletion mice. METHODS AND RESULTS: Hind limb ischemia (HLI) was induced in wild-type (WT) mice transplanted with IP-deleted BM (WT/BM(IP(-/-)). Recovery of blood flow (RBF) in WT/BM(IP(-/-)) was impaired for 28 days after HLI, whereas RBF in IP(-/-)/BM(WT) was attenuated for up to 7 days compared with WT/BM(WT). The impaired RBF in WT/BM(IP(-/-)) was completely recovered by intramuscular injection of WT EPCs but not IP(-/-) EPCs. The impaired effects of IP(-/-) EPCs were in accordance with reduced formation of capillary and arterioles in ischemic muscle. An ex vivo aortic ring assay revealed that microvessel formation was enhanced by accumulation/adhesion of EPCs to perivascular sites as pericytes. IP(-/-)EPCs, in which expression of integrins was decreased, had impaired production of angiogenic cytokines, adhesion to neovessels and their angiogenic effects. The small-interfering RNA (siRNA)-mediated knockdown of integrin ß1 in WT EPCs attenuated adhesion to microvessels and their in vivo and in vitro angiogenic effects. CONCLUSIONS: PGI2 may induce persistent angiogenic effects in HLI through adhesion of EPCs to perivascular sites of neovessels via integrins in addition to paracrine effects.

Acute Myocardial Infarction in a 17-year-old High-school Girl.

We report an unusual case of acute myocardial infarction in a high school girl. The patient was 17 years of age and had multiple coronary risk factors, including marked obesity with a body mass index (BMI) of 42.7 kg/m2, dyslipidemia and glucose intolerance. She had been an on and off smoker since she was 13 years of age. Due to the recent Westernization of the lifestyle, the prevalence of metabolic syndrome in the young generation has been increasing in Japan. Cardiovascular disease based on lifestyle-related diseases may become more common in young people.