Vessel Breakdown Research Articles

Analysis of A-kinase Anchoring Protein 13 (AKAP13) in Peri-Ovulatory Oocyte Maturation [A328

INTRODUCTION: Arrest of oocytes at prophase I of meiosis is crucial for fertility and is maintained by Protein Kinase A (PKA). PKA activity is regulated by A-kinase anchoring proteins (AKAPs) that bind the regulatory subunit of PKA to control enzymatic activity. AKAP13 is expressed in oocytes and granulosa cells of humans and mice. Female mice haploinsufficient for Akap13 showed reduced litter sizes. To determine if AKAP13 in oocytes contributes to female reproductive function, we used an oocyte-specific conditional knockout (cKO) to delete Akap13 in the final stages of oocyte growth. METHODS: Oocytes were collected from mice harboring an oocyte-specific conditional knockout of Akap13 mice, with Cre recombinase expression driven by the Zp3 promoter (Zp3-Cre+, Akap13flox/flox). Akap13 DNA and mRNA were assessed by polymerase chain reaction (PCR) and quantitative PCR (qPCR), respectively. Controls were oocytes harvested from Akap13+/flox mice lacking Cre. Oocytes from control or cKO mice were examined for morphology, meiotic resumption, spindle organization, and spindle positioning at metaphase II. RESULTS: Cre-mediated excision of Akap13 DNA in oocytes was confirmed using PCR. Oocyte mRNA levels of Akap13 in cKO mice were reduced by 90% compared to controls. Live-cell imaging revealed no differences in germinal vessel breakdown, polar body emission, or completion of meiosis I in cKO oocytes as compared to controls. Staining of fixed oocytes revealed that metaphase II spindles and chromosome alignment appeared normal in in vitro-matured cKO oocytes. CONCLUSION: These studies suggest that impairment of female fertility in Akap13 haploinsufficient mice is not caused by impairment of oocyte meiotic maturation.

Muscle injury-induced hypoxia alters the proliferation and differentiation potentials of muscle resident stromal cells

BackgroundTrauma-induced heterotopic ossification (HO) is a complication that develops under three conditions: the presence of an osteogenic progenitor cell, an inducing factor, and a permissive environment. We previously showed that a mouse multipotent Sca1+ CD31− Lin− muscle resident stromal cell (mrSC) population is involved in the development of HO in the presence of inducing factors, members of the bone morphogenetic protein family. Interestingly, BMP9 unlike BMP2 causes HO only if the muscle is damaged by injection of cardiotoxin. Because acute trauma often results in blood vessel breakdown, we hypothesized that a hypoxic state in damaged muscles may foster mrSCs activation and proliferation and trigger differentiation toward an osteogenic lineage, thus promoting the development of HO.MethodsThree- to - six-month-old male C57Bl/6 mice were used to induce muscle damage by injection of cardiotoxin intramuscularly into the tibialis anterior and gastrocnemius muscles. mrSCs were isolated from damaged (hypoxic state) and contralateral healthy muscles and counted, and their osteoblastic differentiation with or without BMP2 and BMP9 was determined by alkaline phosphatase activity measurement. The proliferation and differentiation of mrSCs isolated from healthy muscles was also studied in normoxic incubator and hypoxic conditions. The effect of hypoxia on BMP synthesis and Smad pathway activation was determined by qPCR and/or Western blot analyses. Differences between normally distributed groups were compared using a Student’s paired t test or an unpaired t test.ResultsThe hypoxic state of a severely damaged muscle increased the proliferation and osteogenic differentiation of mrSCs. mrSCs isolated from damaged muscles also displayed greater sensitivity to osteogenic signals, especially BMP9, than did mrSCs from a healthy muscle. In hypoxic conditions, mrSCs isolated from a control muscle were more proliferative and were more prone to osteogenic differentiation. Interestingly, Smad1/5/8 activation was detected in hypoxic conditions and was still present after 5 days, while Smad1/5/8 phosphorylation could not be detected after 3 h of normoxic incubator condition. BMP9 mRNA transcripts and protein levels were higher in mrSCs cultured in hypoxic conditions. Our results suggest that low-oxygen levels in damaged muscle influence mrSC behavior by facilitating their differentiation into osteoblasts. This effect may be mediated partly through the activation of the Smad pathway and the expression of osteoinductive growth factors such as BMP9 by mrSCs.ConclusionHypoxia should be considered a key factor in the microenvironment of damaged muscle that triggers HO.

A Simulation study of sea transport based fertilizer product considering disruptive supply and congestion problems

Every company desires to have an ideal delivery system with no disruption and no downtime. In reality, disruption events cannot be avoided, especially when delivering products using maritime transportation. Such unwanted and uncontrolled events can include sudden factory downtime, vessel breakdown, jetty congestion at a port, and more. Due to the serious consequences, disruption needs to be subjected to considerable scrutiny because it may influence the performance of the company. Many studies have been undertaken regarding inventory routing problems in the maritime area. However, it is very rare that these studies have included disruption events in their model. This research examines supply and transportation disruptions and also develops several scenarios to recover from disruptions so as to increase the system performance. The method used to model this problem is a discrete event simulation, because this tool is capable of handling complex systems. The best alternatives were chosen by finding a compromise or tradeoff between the key performance indicators, specifically the service level and the cost of achieving the goals. Two parameters were tested in the sensitivity analysis to understand the behavior and how sensitive these parameters are to the performance criteria.

TSG-6 is highly expressed in human abdominal aortic aneurysms

BackgroundThe formation of abdominal aortic aneurysms (AAA) is characterized by a dominance of proinflammatory forces that result in smooth muscle cell apoptosis, extracellular matrix degradation, and progressive diameter expansion. Additional defects in the antiinflammatory response may also play a role but have yet to be fully characterized. TSG-6 (TNF-stimulated gene-6) is a potent antiinflammatory protein involved in extracellular matrix stabilization and cell migration active in many pathological conditions. Here, we describe its role in AAA formation. MethodsBlood and/or aortic tissue samples were collected from organ donors, subjects undergoing elective AAA screening, and open surgical AAA repair. Aortic specimens collected were preserved for IHC or immediately assayed after tissue homogenization. Protein concentrations in tissue and plasma were assayed by ELISA. All immune cell populations were assayed using FACS. In vitro, macrophage polarization from monocytes was performed with young, healthy donor PBMCs. ResultsTSG-6 was found to be abnormally elevated in both the plasma and aortic wall of patients with AAA compared with healthy and risk-factor matched non-AAA donors. We observed the highest tissue concentration of TSG-6 in the less-diseased proximal and distal shoulders compared with the central aspect of the aneurysm. IHC localized most TSG-6 to the tunica media with minor expression in the tunica adventitia of the aortic wall. Higher concentrations of both M1 and M2 macrophages where also observed, however M1/M2 ratios were unchanged from healthy controls. We observed no difference in M1/M2 ratios in the peripheral blood of risk-factor matched non-AAA and AAA patients. Interesting, TSG-6 inhibited the polarization of the antiinflammatory M2 phenotype in vitro. ConclusionsAAA formation results from an imbalance of inflammatory forces causing aortic wall infiltration of mononuclear cells leading to the vessel breakdown. In the AAA condition, we report an elevation of TSG-6 expression in both the aortic wall and the peripheral circulation.

Osteopontin Is Elevated in AAA and May Drive Disease Progression

Previous in vitro and animal studies have suggested the importance of osteopontin (OPN), an inflammatory extracellular matrix (ECM) protein, in the formation and growth of abdominal aortic aneurysms (AAAs). The relationship between OPN and the inflammatory cell phenotypes present in the human AAA condition was investigated. Serum OPN concentrations were measured in risk-factor matched non-AAA and AAA patients by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry was used to determine the source of OPN secretion using tissue collected from multiorgan donors and AAA patients undergoing open repair. Vascular smooth muscle cells (VSMCs) were exposed to inflammatory mediators, and the OPN response was evaluated by quantitative RT-PCR and ELISA. The inflammatory nature of OPN and the aortic wall was then determined using a T regulatory cells type 1 (TR1) suppressor cell induction assay. CD45RO– cells were induced to the TR1 suppressor cell phenotype through the action of high-molecular-weight hyaluronan. Inhibition of induction by various compounds was used as a surrogate for inflammatory activity and confirmed by interleukin (IL)-10 ELISA. OPN was elevated in both the plasma (2.08 vs 1.19 ng/mL; P < .05) and the aortic wall homogenate (154.0 vs 38.3 ng/mL; P < .01) of AAAs compared to controls. On immunohistochemistry, OPN localized to the tunica media and VSMCs of the diseased aorta but was not visible in healthy aorta from multiorgan donors. Cigarette smoke extract was the most potent stimulator of OPN secretion in VSMCs and increased supernatant concentration by 2.5-fold and messenger RNA concentration by fourfold over control (P < .05). OPN additionally demonstrated an ability to inhibit the induction of IL-10-secreting TR1 lymphocytes, a depleted population in the AAA patient, from naïve precursors by half (P < .01; Fig). OPN is elevated in the plasma and aortic wall of patients with AAA and is secreted by the VSMCs of the tunica media. It is responsible for inhibition of TR1 cells, decreased IL-10 expression, and an overall proinflammatory environment leading to vessel breakdown and diameter growth. Therefore, inhibition of OPN activity could represent a potential first-in-man pharmaceutical treatment for AAA.

Abstract 109: Tumor Necrosis Factor Inducible Gene 6 Protein (TSG-6) is Highly Expressed in Human Abdominal Aortic Aneurysms

Objective: The formation of an abdominal aortic aneurysm (AAA) is characterized by a dominance of pro-inflammatory forces that result in smooth muscle cell apoptosis, extra-cellular matrix degradation, and progressive diameter expansion. Additional defects in the anti-inflammatory response may also contribute to AAA progression, however have yet to be characterized robustly. Here, we describe the role of the anti-inflammatory cytokine TSG-6 (TNF-stimulated gene-6) in AAA formation. Methods: Blood and aortic tissue samples were collected from patients undergoing elective AAA screening and open surgical AAA repair. Aortic specimens collected were preserved for IHC or immediately assayed after tissue homogenization. Cytokine concentrations in tissue and plasma were assayed by ELISA. All immune cell populations were assayed using FACS analysis. In vitro, macrophage polarization from monocytes were performed with young, healthy donor PBMCs. Results: TSG-6 was found to be abnormally elevated in both the plasma and aorta of patients with AAA compared to healthy and risk-factor matched non-AAA donors. We observed the highest tissue concentration of TSG-6 in the less diseased proximal and distal shoulders compared to the central aspect of the aneurysm. IHC localized the majority of TSG-6 to the tunica media with minor expression in the tunica adventitia of the aortic wall. Higher concentrations of both M1 and M2 macrophages where also observed in the aortic wall, however M1/M2 ratios were unchanged from healthy controls. Additionally, we observed no difference in M1/M2 ratios in the peripheral blood of risk-factor matched non-AAA and AAA patients. Interesting, TSG-6 inhibited the polarization of the anti-inflammatory M2 phenotype in vitro . Conclusions: AAA formation results from an imbalance of inflammatory forces causing aortic wall infiltration of mononuclear cells leading to resultant vessel breakdown. From our results, we suggest TSG-6 is elevated in the AAA patient as a compensatory anti-inflammatory feedback mechanism. However, it’s effects may be abrogated by defects in CD44, its cognate receptor or downstream signaling pathways, future areas for investigation.

A review of vascular disrupting agents as a concomitant anti-tumour modality with radiation

AbstractBackgroundTumour vasculature plays an important role in the development, maintenance and sustainability of a tumour. Endothelial cells which are recruited into the tumour stroma facilitate the formation of essential blood vessels that deliver nutrients and oxygen to tumour cells. A growing body of research is showing that there are synergistic anti-tumour effects when anti-vascular agents are combined with radiation. More recent reports have described favourable radiation response as a function of vascular targeting and blood vessel breakdown, primarily through interactions of radiation with vascular endothelial cells. Vascular disrupting agents are being utilised in several forms that include molecular targeting, biophysical assault and biological interference.PurposeIn the present review, we examine current advances in anti-vascular agents to enhance tumour response when combined with radiation therapy.MethodsA comprehensive literature search was conducted on the US National Library of Medicine, National Institutes of Health (PubMed) using the following search keywords: vascular disrupting agents, radiation sensitisation, anti-angiogenic therapy, anti-vascular therapy, radiation therapy.ConclusionCurrent research suggests the applicability of vascular disrupting agents as an effective radiation sensitisation agent. Pre-clinical and clinical trials have been well developed to form the theoretical framework to apply this powerful modality to the treatment of cancer.

Endometrial bleeding in postmenopausal women

The aim of this study was to present a review of the potential mechanisms involved in the occurrence of endometrial bleeding in postmenopausal women using hormone therapy. Selected literature on the incidence of bleeding in postmenopausal women using estrogen progestogen therapy was reviewed. The incidence of spotting and bleeding in women using continuous-combined hormone therapy was presented. Relevant articles related to the role of angiogenic factors and vasculogenesis in the endometrium, endometrial leukocytes, and endometrial metalloproteinases were used for the review. The cause or etiology of endometrial bleeding with hormone therapy is unknown. Several options are known to alter angiogenesis or be involved in tissue remodeling during normal menstruation. Vascular endothelial growth factor and thrombospondin-1 are proangiogenic and antiangiogenic factors that could cause dysfunction in vasculogenesis that could result in blood vessel fragility and bleeding. The role of pericytes in maintaining vessel morphology and integrity is discussed. Endometrial leukocytes and metalloproteinases are involved in normal menstruation, but their role in postmenopausal bleeding is not clear suggesting involvement of mechanisms in the bleeding. There is limited information on clinical investigation into the etiology of postmenopausal bleeding associated with hormone therapy. The major cause of hormone therapy-related bleeding is unknown. Alterations in angiogenic factors that could result in vascular dysfunction and vessel breakdown provide a working hypothesis as to the potential cause of vessel breakdown.

Divergent regulation of angiopoietin‐1 and ‐2, Tie‐2, and thrombospondin‐1 expression by estrogen in the baboon endometrium

Estrogen has an important role in the reconstruction of a new vascular network in the endometrium during each menstrual cycle; however, the underlying mechanisms are incompletely understood. Angiopoietin-1 (Ang-1) promotes vessel assembly, whereas Ang-2 and thrombospondin-1 (TSP-1) cause vessel breakdown. To determine the potential effect of estrogen on the expression of these angioregulatory factors in the endometrium, Ang-1, Ang-2, TSP-1, and Tie-2 receptor mRNA levels were assessed by real-time reverse transcriptase polymerase chain reaction in glandular epithelial and stromal cells isolated from the endometrium of ovariectomized baboons treated acutely with estradiol. Corresponding protein expression was assessed by immunocytochemistry and the proximity ligation assay (PLA) during advancing stages of the baboon menstrual cycle. Serum estradiol levels in ovariectomized baboons were 400 pg/ml within 4-6 hr of estradiol treatment. Ang-1 mRNA levels in glandular epithelial cells increased threefold (P < 0.01) within 4 hr of estradiol administration. In contrast, TSP-1 mRNA levels decreased four- to fivefold (P < 0.01) in endometrial glandular epithelial and stromal cells 4-6 hr after estradiol, whereas Ang-2 and Tie-2 expression was unaltered. Immunostaining for Ang-1 increased, TSP-1 decreased, and Ang-2 and Tie-2 were unaltered in the endometrium during the secretory compared with the proliferative phase of the cycle. Endometrial Ang-1 protein expression, quantified by PLA, increased 10-fold (P < 0.05) between the early proliferative and late proliferative/mid-secretory phases of the menstrual cycle in association with the rise in estrogen. In summary, estrogen induced a rapid, divergent, and cell-specific change in expression of angiostimulatory and angioinhibitory growth factors in the endometrium of the nonhuman primate.

Possible Pathophysiological Role of Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Metastatic Brain Tumor-associated Intracerebral Hemorrhage

Intratumoral hemorrhage, as one of the cerebrovascular complications in various tumor-related conditions, occurs mainly in malignant brain tumors. Recent studies have shown that the overexpression of vascular endothelial growth factor (VEGF) and metalloproteinase (MMP) may play a role for the loss of vascular integrity and the subsequent hemorrhage in several instances, in addition to their well-known properties in tumor development and metastasis. To investigate the potential role of VEGF and MMP in hemorrhagic complication of metastatic brain tumor, we estimated the expression of VEGF, MMP-2 & -9 by immunohistochemical studies in pathological specimens of metastatic brain tumors obtained from 16 patients, 7 in hemorrhagic and 9 in non-hemorrhagic group. We also examined the expression of collagen type IV, CD34, Factor VIII in order to evaluate the status of tumor vasculature. Patients in hemorrhagic group showed a higher VEGF expression with neovascularization than those in non-hemorrhagic group. The basement membranes of newly formed vessels were disrupted in cases with high expression in both MMP-2 and -9. These results indicate that rapid growing nascent blood vessels, responding vigorously to VEGF, are concentrated around the hemorrhagic tumors. Besides, these results suggest a possibility that the basement membranes of these nascent vessels could be disrupted proteolytically by MMP. We conclude that overexpression of VEGF and MMP may play a role in metastatic brain tumor-associated hemorrhage. Presumably, the underlying pathophysiological mechanisms are through rapid growth and breakdown of vessels around the tumors caused by overexpression of VEGF and MMP of tumor cells.

Steroid receptors in blood vessels of the rhesus macaque endometrium: a review

Estradiol (E) and progesterone (P) act on the primate endometrium to induce dramatic changes in the vascular system during the menstrual cycle. These changes include vessel breakdown and bleeding during menses, heightened angiogenesis during the early proliferative phase, and extensive growth of the spiral arteries in the luteal phase of the cycle. Because steroid hormone action is dependent upon the presence of specific nuclear receptors in target tissues, we used immunocytochemistry with receptor-specific monoclonal antibodies to characterize the spatial and temporal expression of estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor PR and androgen (A) receptor (AR) in the endometrial vessels of rhesus macaques (Macaca mulatta). The only sex steroid receptor that was present in the endothelium and smooth muscle walls of endometrial vessels was ERbeta. ERalpha, PR, and AR were not detectable in either the endothelium or vascular smooth muscle cells of primate endometrial vessels. However, all of these receptors were strongly expressed by the perivascular stroma, and in these cells, all were modulated by the changes in levels of E and P during the cycle. We concluded that any direct effects of E on endometrial vessels would be mediated by ERbeta, and that the actions of P and A, and possibly some of E, were indirectly mediated through perivascular stromal cells.

Surface vascularization and endometrial appearance in women with menorrhagia or using levonorgestrel contraceptive implants. Implications for the mechanisms of breakthrough bleeding.

Women using progestogen-only contraceptives are commonly troubled by irregular bleeding. Endometrial vessel breakdown and repair is thought to be locally regulated under the indirect influence of sex steroids. Most information about endometrial vessels is derived from blind biopsies taken in an outpatient setting. Hysteroscopy allows in-vivo observation of the whole endometrial surface, including vessel morphology, distribution and areas of bleeding, as well as information about non-vascular structures that may not be accessible from biopsies. Hysteroscopies were performed on 34 women using the levonorgestrel contraceptive implant system (Norplant(TM)) and in a comparison group of 20 women complaining of menorrhagia due to ovulatory dysfunctional bleeding. The images were captured and vascular appearances assessed using image analysis. The percentage of the superficial endometrium covered with blood vessels was found to be significantly greater in Norplant users compared with the comparison group (P = 0.0006). More superficial vessels were seen in those with recent frequent or prolonged bleeding and spotting (P < 0.0001). In Norplant users, but not in the comparison group, superficial vascular distribution was predominantly patchy (P < 0.0001). Unusual vascular appearances classified as 'neovascular' (P < 0.0001) and 'mosaic' (P < 0.0001) patterns were commonly seen in Norplant users but not in the comparison group. The hysteroscopic appearance of the endometrial epithelium, glands and stroma also differed between Norplant users and women with menorrhagia. Apparent shedding of the superficial endometrium was commonly seen by hysteroscopy in Norplant users during a bleeding episode (P < 0.0001). Prominent gland openings with thick mucus were commonly seen in Norplant users and small sessile polyps were seen in six cases. These hysteroscopic observations provide further evidence that exposure to progestogens alters the superficial endometrial vasculature and may interfere with angiogenesis.

Mechanisms of abnormal uterine bleeding.

Over the past 10 years there has been an upsurge of interest in the mechanisms underlying normal and disturbed menstrual bleeding. These studies have particularly focused on the mechanisms underlying the common problems of menorrhagia associated with ovulatory and anovulatory dysfunctional uterine bleeding (DUB) and of unpredictable breakthrough bleeding during hormonal contraceptive use. A wide range of abnormalities of endometrial morphology and function have been demonstrated, but it is still not clear how all the pieces of this complex jigsaw puzzle fit together. Ovulatory DUB is predominantly associated with decreased endometrial vasoconstriction and vascular haemostatic plug formation, leading to defective control of the volume of blood which is lost during menstruation. By contrast, breakthrough bleeding is associated with a wide range of molecular disturbances which appear to result in unpredictable vessel breakdown through disturbed endometrial angiogenesis, increased vascular fragility and loss of the integrity of the endothelial, epithelial and stromal supporting structures. Anovulatory DUB is very poorly understood, but may be associated with disturbed angiogenesis, fragile vessels and defective haemostatic processes. Little is known about the actual mechanisms of the common problem of abnormal bleeding associated with specific genital tract pathologies such as uterine myomata.

New Building Production CostsStructure Optimisation

Establishing newbuilding production costs structure represents a fundamental management activity, concerning materials and fabrication in shipbuilding. Shipyards are competing in world market niches, regarding vessel types and dimensions. Therefore, vessel's market price has a tremendous influence at shipyard's determination of vessel price offered to buyers. For this reason shipyard management is forced to concentrate its effort to act upon newbuilding production costs structure optimisation as to achieve the goal of profitable shipyard enterprise. In this paper, a computer integrated mathematical model of costing engineering of vessel production founded by authors is presented. Model concept is based on both, functional and technological, vessel breakdown structures. Statistical analysis of data was performed for a sample of tankers population, built in Croatian shipyards. Probabilistic theory was applied and several results such as of expectation for aggregate figures are presented. Such developed tool for obtaining an optimal production costs structure enables shipyard management besides more successful managing and decision making, also latter through the process a better costs control within model parameters. Dynamical control is needed of costing figures within optimised structure of production costs, that for assigned conditions, for the whole shipbuilding process and product, have significant influence upon performance final results. Mathematical model for achieving optimal structure of production costs was verified and tested against real example for tanker newbuilding. Transactions on the Built Environment vol 42, © 1999 WIT Press, www.witpress.com, ISSN 1743-3509

Cerebral amyloid angiopathy: prospects for clinical diagnosis and treatment.

This article reviews diagnosis of cerebral amyloid angiopathy (CAA) during life and possible approaches to prevention. A clinical diagnosis of "probable CAA" can be made in patients aged 60 years or older with multiple hemorrhages confined to lobar brain regions and no other cause of hemorrhage. Gradient-echo MRI facilitates diagnosis by showing previous hemorrhages with high sensitivity. This technique can also mark the progression of CAA, as 50% of studied patients developed new petechial hemorrhages during 1.5 years of follow-up. The apolipoprotein E epsilon2 and epsilon4 alleles are associated with increased risk and earlier age of first hemorrhage, but are neither sensitive nor specific for CAA. The major remaining challenges are to develop new markers for the presence of CAA and treatments to block vascular amyloid deposition and vessel breakdown.

Skeletal muscle fiber, nerve, and blood vessel breakdown in space‐flown rats

Histochemical and ultrastructural analyses were performed postflight on hind limb skeletal muscles of rats orbited for 12.5 days aboard the unmanned Cosmos 1887 biosatellite and returned to Earth 2 days before sacrifice. The antigravity adductor longus (AL), soleus, and plantaris muscles atrophied more than the non-weight-bearing extensor digitorum longus, and slow muscle fibers were more atrophic than fast fibers. Muscle fiber segmental necrosis occurred selectively in the AL and soleus muscles; primarily, macrophages and neutrophils infiltrated and phagocytosed cellular debris. Granule-rich mast cells were diminished in flight AL muscles compared with controls, indicating the mast cell secretion contributed to interstitial tissue edema. Increased ubiquitination of disrupted myofibrils implicated ubiquitin in myofilament degradation. Mitochondrial content and succinic dehydrogenase activity were normal, except for subsarcolemmal decreases. Myofibrillar ATPase activity of flight AL muscle fibers shifted toward the fast type. Absence of capillaries and extravasation of red blood cells indicated failed microcirculation. Muscle fiber regeneration from activated satellite cells was detected. About 17% of the flight AL end plates exhibited total or partial denervation. Thus, skeletal muscle weakness associated with spaceflight can result from muscle fiber atrophy and segmental necrosis, partial motor denervation, and disruption of the microcirculation.