The consequences of orthodontic extrusion on previously intruded permanent incisors-A retrospective study.

AIM: The aim of this study is to compare the adverse effects that occur after orthodontic extrusion of teeth that have been traumatically intruded with those of similar teeth that have not experienced any trauma. BACKGROUND: The outcome of incisors intrusion can be affected by the patient's age, extent of injury, root development, and malocclusion. Orthodontic extrusion is a potential solution, but it may also cause complications. MATERIALS AND METHODS: A retrospective study of the effects of extrusion of traumatically intruded teeth was carried out. The study group included 21 teeth in 14 patients. The control group included 32 teeth in 10 patients that underwent orthodontic extrusion with no history of trauma. Patients' age, gender, and stage of root development were recorded. The severity of the intrusion was classified as mild (<3 mm), moderate (3-6 mm), and severe (≥7 mm). A comparison of signs of pulp necrosis and root resorptions between the groups was made. RESULTS: The central incisor is the tooth that is most injured in 80.9% of cases. A majority of these incidents involve severe intrusion, which was found in 42.9% of cases. 90% of the traumatized teeth had already lost their vitality prior to orthodontic treatment. Various forms of root resorption were observed in the study group. In the control group, 31.2% of teeth showed signs of external root resorption, but no endodontic intervention was carried out during the follow-up period, as these teeth remained vital. CONCLUSIONS: Following intrusion, there is a high risk for root resorption and pulp necrosis. Orthodontic repositioning should be carried out with caution and mild force to prevent complications. Long-term follow-ups are required to ensure the best possible outcome.

Regenerative Endodontic Procedures in Immature Teeth Affected by Regional Odontodysplasia.

INTRODUCTION: Regional odontodysplasia (ROD) is a rare developmental disorder characterized by hypo-mineralization and hypoplasia of enamel and dentin. Symptoms include poorly developed tooth buds, delayed eruption of permanent teeth in affected quadrants, and ghost teeth. The affected teeth often become necrotic due to abnormal enamel and dentin development, making them susceptible to caries and infection. The aim of this case report is to describe the treatment of ROD through pulp revascularization. CASE REPORT: A 13-year-old girl was referred for endodontic treatment. The mandibular left incisors and first premolar, which were affected by regional odontodysplasia, lost their vitality because of the impaired structure of the enamel. Due to the teeth's early developmental stage, a regenerative endodontic treatment was attempted. All 3 teeth were treated using the same protocol following the AAE guidelines. After 4 weeks, treatment of the premolar was completed, whereas the incisor teeth remained symptomatic and were and therefore, intracanal dressing with calcium hydroxide was repeated and left in place for 5 months. Finally, the regenerative procedure was completed, and the crowns were restored. The patient was scheduled for follow-up examinations after 6 months, and then yearly for the next 3 years. After 1 year, the periapical lesion around the central incisor and premolar had resolved, the lesion around the apex of the lateral incisor was healing, and the roots had continued to develop. After 3 years, complete healing and pulp canal obliteration were observed in the central incisor and in the premolar. However, the root of the lateral incisor tooth was split, and it was recommended to extract this tooth. CONCLUSION: The positive outcomes of regenerative endodontics in the central incisor and premolar suggest that revascularization of the pulp may be optional for the treatment of immature necrotic teeth affected by developmental disorders, such as ROD, amelogenesis imperfecta, or dentinogenesis imperfecta.

The Outcome of Decoronation in Severe Cases of External Cervical Root Resorption in Young Patients.

This study examines decoronation as a treatment option for teeth with progressive external cervical root resorption (ECR). Six young patients aged 9.5-13, with a total of nine incisor teeth affected by ECR due to previous dental trauma, were treated by decoronation. Six teeth were classified as class 4 and two as class 3, according to Heithersay's classification. Another tooth with class 2 resorption also had a perforation. After decoronation, all cases showed favorable outcomes during a follow-up period of 2.5-8 years. The procedure halted the progression of ECR and promoted vertical and horizontal ridge development above the submerged root. Decoronation can be considered for the successful treatment of advanced cases of ECR in young patients.

Altered sensation following extrusion of an endodontic file treated by intentional replantation: case report and treatment recommendations.

OBJECTIVE: An altered sensation during endodontic treatment can occur due to the extrusion of endodontic materials. This study aims to discuss intentional replantation to address paresthesia resulting from an endodontic file penetrating the inferior alveolar nerve canal (IANC) and provide a protocol for managing nerve injuries in such incidents. CASE PRESENTATION: A 12-year-old girl developed paresthesia when an endodontic file separated and was inadvertently pushed through the apical foramen into IANC during root canal treatment of the mandibular left first molar. A CBCT scan revealed the file penetrating the canal towards the inferior border of the mandible. After considering the treatment options, intentional replantation was deemed suitable. The tooth was a-traumatically extracted and preserved in sterile saline. The surgeon then carefully cleaned and irrigated the socket. The radiographic assessment confirmed successful file removal from the socket. The Root ends were resected, and retrograde preparation and obturation were conducted using ultrasonic tips and MTA. The tooth was then replanted into the socket. Successful replantation was confirmed by tooth stability and an audible click. The patient was prescribed antibiotics and steroids. Subsequently, after completing the endodontic treatment. a stainless-steel crown was cemented. The successful intentional replantation procedure resulted in rapid improvement in the patient's condition. The normal sensation had been restored, indicating nerve recovery. At the 15-month follow-up, Periapical bone healing and the eruption of the adjacent second molar were observed, affirming the treatment protocol's overall success. CONCLUSION: Prompt intervention and immediate intentional replantation facilitated direct inspection of the separated file within the socket. Collaboration between an oral maxillofacial surgeon and an endodontist ensures expedited and targeted treatment, leading to favorable outcomes.

Enhanced socket preparation during autotransplantation: a new treatment protocol.

OBJECTIVE: Tooth autotransplantation (AT) is a viable option for the replacement of unrestorable or missing teeth. Recently, the use of a 3D replica of a donor tooth constructed from CBCT scans was described. The model is made to assess the recipient site's size and minimize the required extraoral time of the donor tooth after extraction. The aim of the paper was to describe a new technique for AT using the 3D replica as a socket preparation tool. CASE REPORT: A 13-year-old boy who presented with hypodontia was referred for consultation and treatment. The treatment plan included combined orthodontic treatment and AT of the mandibular left second premolar into the site of the congenitally missing maxillary right canine. A titanium 3D model of the donor tooth was printed by a direct metal laser 3D printer utilizing the model from the CBCT scan. An intrasulcular flap was elevated, and the edentulous maxillary ridge was prepared using implant trephine burs with increasing diameters. A surgical mallet was utilized to apply vertical forces to the 3D-printed model, which was inserted into the prepared socket to allow a perfect fit for the donor tooth. After atraumatic extraction of the mandibular left second premolar, the donor tooth was inserted into the ready socket and splinted. Follow-up examinations at 1, 3, and 6 months, and 1 year after surgery demonstrated a successful outcome. CONCLUSION: The titanium replica was successfully used for precise preparation of the recipient site, minimizing the extraoral time of the procedure to 4 minutes, and thereby improving the expected outcome. (Quintessence Int 2023;54:142-148; doi: 10.3290/j.qi.b3649031).

An Assessment of the Effects of Orthodontic Treatment after Apexification of Traumatized Immature Permanent Teeth: A Retrospective Study.

INTRODUCTION: Root resorption may occur in traumatized necrotic teeth that have undergone apexification after orthodontic treatment. This study examined the effects of orthodontic treatment on the outcome of apexification. METHODS: This retrospective study included 36 children presenting with anterior permanent traumatized teeth with immature roots who were treated by apexification and root canal treatment. The orthodontic group consisted of 17 children with 24 teeth that were subjected to orthodontic treatment after apexification. The control group consisted of 19 children with 21 teeth that underwent only apexification without orthodontic treatment. Almost half of the teeth in both groups underwent apexification with calcium hydroxide, whereas the other half were treated with mineral trioxide aggregate. The effects of sex, stage of root development, and apexification material on the outcomes of apexification were analyzed and compared between the 2 groups. RESULTS: Apexification was successful in 88% of cases after at least 5 years of follow-up. Neither apexification technique nor sex had a significant effect on treatment outcome. The stage of root development had a positive effect on outcome, although it was not statistically significant. Some root resorption (average = 0.3 mm) was observed after orthodontic treatment, whereas teeth that underwent apexification without orthodontic treatment exhibited some root elongation (average = 0.1 mm). This difference was highly significant. CONCLUSIONS: Minor root resorption was observed in the orthodontic group compared with a minor increase in root length in the control group. Orthodontic movement of immature traumatized teeth after apexification appears to be safe.

Vitamin A deficiency associated with enhanced proliferation of bile duct epithelial cells in the rat.

BACKGROUND: Vitamin A and its derivative retinoic acid regulate various aspects of cell behavior as growth, differentiation, and proliferation. Retinoic acid derivative have been suggested to play a role in processes such as hepatic regeneration and fibrosis. OBJECTIVES: To evaluate the influence of vitamin A on rat liver epithelial cell proliferation. METHODS: We performed common bile duct ligation in rats that had been subjected to differing vitamin A diets and compared their livers to control rats. Proliferation, apoptosis, and retinoic acid receptors were evaluated by histology and immunohistochemistry in bile duct cells and hepatocytes. RESULTS: Vitamin A deficiency was found to be associated with enhanced proliferation of bile duct epithelial cells following CBD ligation. The proliferation was manifested by increased numbers of ducts, by aberrant extended ductal morphology, and by elevated numbers of nuclei expressing the proliferation marker Ki67. The amount of vitamin A in the rat diet did not affect detectably ductal cell apoptosis. We observed up-regulated expression of the retinoid X receptor-alpha in the biliary epithelium of vitamin A-deficient rats that had undergone CBD ligation, but not in vitamin A-sufficient rats. CONCLUSIONS: We speculate that the mechanism underlying the ductal proliferation response involves differential expression of RXR-alpha. Our observations suggest that deficiency of vitamin A may exacerbate cholestasis, due to excessive intrahepatic bile duct proliferation.

The effect of CO2 Laser on the permeability of dentinal tubules: a preliminary in vitro study.

OBJECTIVES: The purpose of this in vitro study was to determine whether there is a change in dentin permeability following 9.6-microm CO(2) laser irradiation and high-speed drilling. MATERIALS AND METHODS: Twenty permanent, intact, non-carious molars were selected. The crowns were separated from the roots at the cemento-enamel junction. The teeth were randomly divided into two groups, control and experimental, each containing 10 teeth. After class I preparation using a high-speed drill, 9.6-microm CO(2) laser irradiation was applied to dentinal areas only on the experimental group. The samples were soaked in 0.5% methylene blue for 48 h; three independent examiners using scanning electron microscopy evaluated dye penetration through the specimens. RESULTS: The results of the three examiners were similar. There was a significant difference in dye penetration into dentin after laser irradiation versus controls (p < 0.05). CONCLUSIONS: The 9.6-microm CO(2) laser appears to be a promising tool in the clinical setting. However, further investigation is needed to ensure maximum effectiveness.

The effect of CO(2) laser on the microhardness of human dental hard tissues compared with that of the high-speed drill.

OBJECTIVE: The purpose of this study was to examine the effect of 9.6-microm CO(2) laser energy on the microhardness of human dental hard tissues compared with that of high-speed drill cavity preparation, and to determine the applicability of this laser in clinical treatment. MATERIALS AND METHODS: A total of 10 caries-free human single-rooted teeth were used for this study. The crowns were resected and the roots were longitudinally sectioned into two halves. In each slice one half of the enamel and the dentin were treated with 9.6-microm CO(2) laser irradiation, and in the other half the enamel and dentin were treated with a high speed drill, each half for 3 s. Following treatment, the samples were polished and tested for microhardness. The results were compared using analysis of variance. RESULTS: Statistically significant differences in dentin microhardness were found between specimens treated with 9.6-microm CO(2) laser energy as compared with specimens treated with the high-speed drill (p = 0.0156). There were no statistically significant differences in enamel microhardness between specimens treated with 9.6-microm CO(2) laser energy and specimens treated with the high-speed drill. CONCLUSION: The clinical use of 9.6-microm CO(2) laser energy for cavity preparation should be further analyzed, and compared with different types of lasers used in dentistry, such as 10.6-microm CO(2) or Er-YAG.

Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta2-glycoprotein-I (beta2GPI). The factors causing production of anti-beta2GPI remain unidentified, but an association with infectious agents has been reported. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-beta2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-beta2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of antipeptide [TLRVYK] anti-beta2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-beta2GPI mAb. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with beta2GPI induce pathogenic anti-beta2GPI Ab's along with APS manifestations.

Transcription-controlled gene therapy against tumor angiogenesis.

A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell-specific apoptosis, using adenoviral vector-mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-alpha. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1-based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.

Orbital marginal zone lymphomas: an immunohistochemical, polymerase chain reaction, and fluorescence in situ hybridization study.

Many studies have been performed on chromosomal aberrations of extranodal marginal zone lymphomas. However, only a few have been published so far on ocular adnexal marginal zone lymphomas. We studied 18 cases of orbital lymphoid cell infiltrates. Using fluorescence in situ hybridization (FISH), we studied some of the most common chromosomal aberrations found in extranodal marginal zone lymphomas as: trisomies 3, and rearrangements of the 18q21 MALTI gene to detect the translocations t(11;18)(q21;q21) and t(14;18)(q32;q21)MALT1. Our goals were as follows: (1) study those aberrations in our material and compare them with the literature, (2) check their prognostic significance, and (3) check whether studying those aberrations with FISH can be used as a diagnostic tool to differentiate reactive from neoplastic infiltrates, in addition to immunohistochemistry and polymerase chain reaction. We found a high frequency of trisomies 3 (68%) and 18 (56.6%), the highest published so far in orbital lymphomas. On the other hand, no rearrangement was seen in any of our cases. The histologic picture and the clinical course were the same when there was one or more aberrations. As for the diagnostic significance, the presence of a prior, concurrent, or subsequent lymphoma in almost all the positive for aberrations cases suggests that either the orbital infiltrates in these cases are lymphomas, or they have, at least, a malignant potential or a genetic instability. Therefore, the demonstration of these numerical aberrations by FISH may be an additional sensitive, reliable, and relatively simple tool to differentiate reactive from neoplastic orbital lymphoid cell infiltrates when the immunohistochemistry and polymerase chain reaction, performed in a busy and routine-based histopathology laboratory, are unsatisfactory.

Healing of a fibrous dysplastic lesion in a permanent molar after endodontic therapy.

Fibrous dysplasia presents in two forms: monostotic and polyostotic. Both forms are more widespread among children and juveniles and may result in facial asymmetry. Neoplastic bone lesions, localized over the root apices and mimicking periapical pathosis, have been observed. Irregular pulp morphology not previously reported is described in the following case report. A 14-year-old boy diagnosed with fibrous dysplasia was referred for endodontic treatment as the result of a necrotic pulp in an upper molar. A periapical lesion was diagnosed when the tooth was intact. After complex root canal treatment the periapical lesion healed.

Retrieval of amalgam from the root canal space.

Removal of foreign objects from the root canal can be very frustrating. The use of a variety of instruments and techniques has been suggested for the retrieval of obstacles from root canals during endodontic treatment. This article describes a method for retrieving a large mass of amalgam restoration that was wedged into the root canal. The amalgam, which had served as the provisional restorative material during apexification of an immature ante rior tooth, was inadvertently pushed into the root canal. After the mass was bypassed, the amalgam was loosened with the aid of copious irrigation, chelation, and flotation. Hedstrom files twisted around the object allowed sufficient grip for its retrieval, enabling completion of the root canal treatment.

Nuclear factor-kappaB protects the liver against genotoxic stress and functions independently of p53.

p53 and NF-kappaB are two key effectors in the chemotherapy-induced genotoxic response. Although p53 is a universal inducer of apoptotosis in many stress responses, including the genotoxic response, the role of nuclear factor (NF)-kappaB is not consistent and was reported to both counteract and mediate apoptosis. Although the reason for the apparent contradictory effects of NF-kappaB is not understood, it may partly be related to the reported cross-regulation of NF-kappaB and p53. Thus far, all studies exploring the cross-talk between p53 and NF-kappaB in conjunction with apoptosis have been performed in tissue-cultured cells and may therefore not faithfully represent conditions that prevail within a chemotherapy-subjected organism. To address this concern, we examined the respective roles of NF-kappaB and p53 in a liver model of doxorubicin-induced DNA damage. Using this animal model, we report that NF-kappaB is activated in response to doxorubicin-induced genotoxic stress and exerts a pronounced protective effect in opposing chemotherapy-induced tissue damage. Importantly, the activation of NF-kappaB occurs independently of p53 status. Furthermore, although p53 is also induced in this in vivo system, its induction is independent of NF-kappaB and does not contribute to the extent of tissue damage. These findings may have important implications with respect to the potential use of NF-kappaB modulators in cancer therapy.

Sil overexpression in lung cancer characterizes tumors with increased mitotic activity.

Sil (SCL interrupting locus) was cloned from the most common chromosomal rearrangement in T-cell acute lymphoblastic leukemia. It is an immediate early gene whose expression is associated with cell proliferation. Sil protein levels are tightly regulated during the cell cycle, reaching peak levels in mitosis and disappearing on transition to G1. A recent study found Sil to be one of 17 genes whose overexpression in primary adenocarcinomas predicts metastatic spread. We hypothesized that Sil might have a role in carcinogenesis. To address this question, we utilized several approaches. Using a multitumor tissue array, we found that Sil protein expression was increased mostly in lung cancer, but also at lower levels, in a subset of other tumors. Microarray gene expression analysis and immunohistochemistry of lung cancer samples verified these observations. Sil gene expression in lung cancer correlated with the expression of several kinetochore check-point genes and with the histopathologic mitotic index. These observations suggest that overexpression of the Sil gene characterizes tumors with increased mitotic activity.

Functional inhibition of Ras by S-trans,trans-farnesyl thiosalicylic acid attenuates atherosclerosis in apolipoprotein E knockout mice.

BACKGROUND: Atherosclerosis is a multifactorial disorder involving inflammatory processes. These responses are associated with robust activation of signaling cascades by diverse cell surface receptors in a variety of cell types. The processes that are involved in atherosclerosis would likely require intact Ras pathways, which play a key role in the control of cell growth, differentiation, and apoptosis. METHODS AND RESULTS: We examined whether the Ras inhibitor farnesyl thiosalicylic acid (FTS) can suppress atherogenesis in the apolipoprotein E-deficient mouse model. Mice were treated with FTS or a control regimen 3 times weekly for 6 weeks and fed a normal chow diet. Two additional groups included FTS-treated and control-treated mice that were fed a high-fat diet for 10 weeks. FTS reduced both fatty streaks and advanced lesions compared with the control treatment. Ras inhibition in vivo was evidenced by the reduced content of the active form of Ras (Ras-GTP) in aortas of FTS-treated mice. Splenocytes from the FTS-treated versus control mice exhibited reduced proliferation to oxidized LDL (OxLDL) but not to concanavalin A. IgG anti-OxLDL antibody levels were reduced in FTS-treated mice compared with controls. Whereas no effect of FTS was evident on plaque T lymphocyte and macrophage content, lesional vascular cell adhesion molecule-1 and nuclear factor-kappaB expression were considerably reduced compared with controls. CONCLUSIONS: FTS suppressed atherosclerotic plaques in apolipoprotein E-deficient mice, providing a useful tool for research in atherosclerosis.

Variation in gene expression patterns in effusions and primary tumors from serous ovarian cancer patients.

BACKGROUND: While numerous studies have characterized primary ovarian tumors, little information is available regarding expression patterns of metastatic sites of this cancer. To define sets of genes that distinguish primary and metastatic ovarian tumors, we used cDNA microarrays to characterize global gene expression patterns in 38 effusions (28 peritoneal, 10 pleural) and 8 corresponding primary ovarian tumors, and searched for associations between expression patterns and clinical parameters. RESULTS: We observed multidimensional variation in expression patterns among the cancers. Coordinate variation in expression of genes from two chromosomal regions, 8q and 19q, was seen in subsets of the cancers indicating possible amplifications in these regions. A set of 112 unique genes of known function was differentially expressed between primary tumors and effusions using supervised analysis. Relatively few differences were seen between effusions isolated from the pleural and peritoneal cavities or between effusions from patients diagnosed with stage III and stage IV cancers. A set of 84 unique genes was identified that distinguished high from lower grade ovarian cancers. The results were corroborated using immunocytochemistry, mRNA in situ hybridization, and immunoblotting. CONCLUSION: The extensive variation in expression patterns observed underscores the molecular heterogeneity of ovarian cancer, but suggests a similar molecular profile for ovarian carcinoma cells in serosal cavities.

Inhibition of carcinogenesis in transgenic mouse models over-expressing 15-lipoxygenase in the vascular wall under the control of murine preproendothelin-1 promoter.

Oxygenases are a family of enzymes that dioxygenate unsaturated fatty acids, thus initiating membrane oxidation and signaling molecule synthesis. The lipoxygenases (LOs), a family of lipid-peroxidizing enzymes that induce structural and metabolic changes in the cell in a number of pathophysiological conditions, belong to the oxygenases family. This class of enzymes has several subgroups, named 5-, 8-, 12- and 15-LOs, and these LO-isoforms are capable of oxygenating arachidonic and linoleic acid. 15-LOs were reported to play an inhibitory role in tumor angiogenesis and, consequently, they slow down carcinogenesis. It has been suggested that its anti-carcinogenic effect is conferred by promoting cell differentiation and apoptosis. Using transgenic mice that over-express 15-LO-1 in endothelial cells under the regulation of the murine preproendothelin-1 promoter, we studied its effect on tumor and metastasis growth. We found that 15-LO-1 inhibited tumor and metastasis growth in the transgenic mice in two different models of cancer (mammary gland and Lewis lung carcinoma). This inhibition was concomitant with a higher number of apoptotic cells in the metastases of the transgenic mice and with a complicated network of multiple small blood vessels. This finding targets 15-LO as a new candidate in the treatment of carcinogenesis.

Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression.

OBJECTIVE: Factor XIII (FXIII), a plasma transglutaminase that stabilizes fibrin clots at the final stages of blood coagulation by crosslinking fibrin monomers, is essential for embryo implantation and participates in tissue remodeling and wound healing, processes that involve angiogenesis. The aim of our study was to analyze the effect of FXIII on angiogenesis using in vitro and in vivo models and to examine the role of FXIII in the basic steps of angiogenesis, ie, migration, proliferation, and apoptosis/cell survival. METHODS AND RESULTS: In the Matrigel tube formation model, only FXIIIa caused a dose-dependent enhancement of array formation. This proangiogenic effect was not associated with alterations in vascular endothelial growth factor (VEGF) protein levels nor VEGF or VEGFR2 mRNA levels. FXIIIa, but not nonactivated or transglutaminase-inactivated FXIII, significantly enhanced endothelial cell migration and proliferation and inhibited apoptosis. After treatment of HUVECs with FXIIIa, almost complete disappearance of mRNA of thrombospondin 1 (TSP-1) and a marked reduction in the secretion of TSP-1 protein were observed. A reduction in TSP-1 protein synthesis, although to a lesser extent, was observed on treatment of microvascular endothelial cells with FXIIIa. In a rabbit cornea model, injection of FXIIIa caused neovascularization associated with almost complete disappearance of TSP-1 in the cornea. CONCLUSIONS: These results show that FXIIIa exhibits a novel proangiogenic activity that is associated with downregulation of TSP-1 and also involves stimulation of endothelial cell proliferation and migration and inhibition of apoptosis. These findings might shed light on the mechanism by which FXIII mediates tissue repair and remodeling.