Ephemeral streams with spatially and temporally variable flow are important ecological settings in semi-arid desert environments that until now have been poorly characterized. Our quantitative analysis explores how intermittent stream hydrology varies across geomorphic (mountain streams to desert washes) and climatic gradients (150-400 mm precipitation) in Southern Arizona. Stream channels were instrumented for the first time with a co-deployment of vertical profiles of subsurface temperature sensors, and electrical resistance (ER) sensors on the bed surface. HYDRUS 1-D was used to simulate vertical unsaturated flow, and differences along hydrologic, topographic, and climatic gradients were compared. Annual surface water presence varied < 1%-82% of the year, and reach-normalized infiltration water volumes were 20,000-2,500,000 m³/(km y). Surface water presence was correlated with geomorphic gradient, and infiltration volumes were correlated with surface water presence. This sensor co-deployment method has shown that ER sensors alone are necessary to estimate infiltration in semi-arid, poorly-sorted, coarse desert channels.

Ingesting carbohydrate (CHO) before and during prolonged steady-state exercise can significantly improve the endurance capacity (time to exhaustion) of adolescents. This knowledge, combined with current understanding of the physiological and metabolic responses of young people to prolonged steadystate exercise, as well as awareness of youth team games participation statistics, suggests CHO ingestion before and during team games exercise may be beneficial for adolescent team games players. However, research in this area has not been conducted, presenting a notable gap in the paediatric exercise science literature. This thesis described three studies with the aim of investigating the influence of CHO ingestion immediately before, and during, prolonged intermittent, high-intensity exercise on the endurance capacity, sprint performance, and physiological responses of adolescent team games players. The studies investigated a CHO-electrolyte (CHO-E) solution, solutions of differing CHO concentration ([CHO]), and CHO in the form of a gel in trained 12-14 year old soccer, rugby, and field hockey players during a modified Loughborough Intermittent Shuttle Test (LIST). Study 1 (n = 15) reported a significant 24.4% enhancement of intermittent endurance capacity with ingestion of a 6% CHO-E solution compared with a placebo (PLA, 5.1 ± 1.8 vs. 4.1 ± 1.6 min, P < 0.05, r = 0.51), with distance covered also significantly greater in the CHO trial (851 ± 365 vs. 694 ± 278 m, P < 0.05, r = 0.52). No significant influence of CHO was found for mean sprint times (P = 0.35, r = 0.27) or physiological response except at exhaustion, where peak heart rate was significantly greater in the CHO trial (P < 0.05, r = 0.55). Study two (n = 7) found a significant influence of [CHO] on intermittent endurance capacity, with a 6% solution increasing intermittent endurance capacity by 34.1% compared with a 10% solution (5.5 ± 0.8 vs. 4.1 ± 1.5 min, P < 0.05, r = 0.76). No significant difference was observed between the 2% (4.8 ± 1.2 min) and the 6% (P = 0.10, r = 0.63), or the 2% and the 10% (P = 0.09, r = 0.63) solution. Distance covered was significantly greater with the 6% solution compared with the 10% solution (931 ± 172 vs. 706 ± 272 m, P < 0.05, r = 0.76), but was not significantly different compared with the 2% solution (811 ± 230 m, P = 0.09, r = 0.63) or between the 2% and 10% solutions (P = 0.11, r = 0.61). Carbohydrate concentration did not significantly influence mean sprint times (P = 0.38, r = 0.42) or physiological response. Study three (n = 11) reported a significant 21.1% enhancement in intermittent endurance capacity with ingestion of a CHO gel, isoenergetic to the 6% CHO-E solution used in studies 1 and 2, compared with a PLA gel (4.6 ± 2.0 vs. 3.8 ± 2.4 min, P < 0.05, r = 0.67). Distance covered was also significantly greater in the CHO trial (787 ± 319 vs. 669 ± 424 m, P < 0.05, r = 0.57). No influence of the CHO gel was observed on mean sprint times (P = 0.33, r = 0.31) or physiological response. This thesis reports a significant positive influence of CHO ingestion on the intermittent endurance capacity of adolescent team games players during prolonged intermittent, high-intensity exercise. Ingestion of a 6% CHO-E solution was more beneficial than a PLA solution and a 10% CHO-E solution. When compared to a PLA gel, CHO gel ingestion was analogous in efficacy to a 6% CHO-E solution. Carbohydrate ingestion did not significantly influence sprint performance. The influence of CHO on the physiological responses of adolescent team games players to prolonged intermittent, high-intensity exercise was minimal, with the only reported effect being a significantly greater HR at exhaustion in study 1. This thesis has provided evidence to support the use of CHO before and during team games in adolescent team games players, begun to formulate guidelines for CHO ingestion by adolescent team games players, and provided a robust foundation for further study in this field.

Sucrose fading and intermittent access are two common procedures that induce alcohol consumption in rodents. Sucrose fading procedures involve exposing ethanol naïve rats to a mixture of ethanol and sucrose and gradually reducing the concentration of sugar. Intermittent access procedures involve providing rats with access to ethanol on alternating days. Given that rats will consume ethanol without sucrose, the role of sugar in the sucrose fading procedure is unclear. Rats must be ethanol naïve when they are exposed to treatment with sucrose fading, so there is no point of comparison to show that exposure to sugar in sucrose fading produces higher levels of drinking. There has yet to be any work that isolates the effects of sugar on the consumption of alcohol. The purpose of the present experiment was to examine the effects of sucrose on ethanol consumption in rats with different alcohol histories. Two groups of six rats were exposed to two successive sucrose fading procedures, 30 days apart and their drinking was measured 30 days after each one. One group was exposed to an intermittent access procedure to establish drinking prior to treatment with sucrose fading, the other was ethanol naïve. Following sucrose fading, all rats drank pharmacologically active doses of ethanol. For both groups consumption correlated with the concentration of sucrose and decreased in a step-wise manner as it was faded. For the ethanol experienced rats, consumption dropped below baseline levels as sucrose was faded and decreased further with the second exposure. In contrast, the ethanol-naïve rats did not decrease consumption from the first sucrose fading procedure to the second. Slight differences in peak force of responses were also observed.

As dietas intermitentes (IF) compreendem ciclos alternados de 24 horas de jejum e alimentação. Como os efeitos de IF sobre o balanço redox não são bem conhecidos, esse trabalho teve por objetivo avaliar os efeitos desta dieta sobre o estado redox de diferentes tecidos de ratos. Após um mês de tratamento, os fígados dos ratos em IF apresentaram um aumento de capacidade respiratória mitocondrial juntamente com níveis elevados de proteínas carboniladas. Verificou-se ainda um aumento em danos oxidativos no cérebro destes animais. IF promoveu significativa proteção contra danos oxidativos no coração, enquanto que não houve alterações no estado redox do músculo esquelético. Os efeitos metabólicos de IF também foram investigados com o intuito de compreender os mecanismos envolvidos com o menor peso e a hiperfagia promovidos por esta intervenção. Observou-se que o menor peso dos ratos submetidos à IF é consequência de um aumento em taxas metabólicas em dias de alimentação somado à oxidação lipídica aumentada durante o jejum. A hiperfagia, por sua vez, é consequencia de elevação nos níveis de neurotransmissores orexigênicos hipotalâmicos, mesmo quando estes animais estão alimentados. Os níveis do neutransmissor TRH também foram modulados por esta dieta, o que pode estar relacionado com as alterações de taxas metabólicas observadas no modelo. Concluímos, portanto, que as dietas intermitentes promovem modificações funcionais no hipotálamo que estão associadas com diferenças no peso corpóreo e no apetite. Além disso, IF afeta o balanço redox de forma tecido específica, levando a um desbalanço oxidativo no fígado e no cérebro e à proteção contra danos oxidativos no coração. / Intermittent fasting (IF) is a dietary intervention that comprises 24 hour cycles alternating ad libitum feeding and fasting. We address here the effects of IF on redox state in different tissues, which are still poorly understood. After one month on the diet, IF rats livers presented increased mitochondrial respiratory capacity along with increased levels of protein carbonyls. Surprisingly, IF animals also presented an increase in oxidative damage in the brain. Conversely, IF promoted a substantial protection against oxidative damage in the heart. No difference in redox homeostasis was observed in the skeletal muscle. We also assessed metabolic effects of IF to uncover the mechanisms involved in the lower body mass and loss of feeding control in IF rats. As measured calorimetrically, IF animals presented high metabolic rates during feeding days and increased lipid oxidation on fasting days, which explains the lower body weight. IF-induced overeating was a consequence of increased expression of hypothalamic orexigenic neurotransmitters, even on feeding days. THR levels also were changed, in parallel with the feeding-dependent alterations on metabolic rates. Overall, we find that intermittent fasting promotes functional hypothalamic alterations associated with differences in body weight and appetite. In addition, IF affects redox balance in a tissue-specific manner, leading to redox imbalance in the liver and brain, as well as protection against oxidative damage in the heart

Muscle fatigue is universally experienced in daily life, from recreational physical activity to the workplace. However, our ability to estimate fatigue is limited. Several attempts have been made to mathematically model the effects of fatigue, such as how long a muscle contraction may be sustained, known as `endurance time.' However, these simple models of endurance time are limited to static contractions when the body is not moving, but muscles are contracted. This research aims to advance a previously proposed analytical model of muscle fatigue to represent complex tasks such as with rest intervals and dynamic contractions. Multiple methodologies were employed to assemble data to examine the model prediction accuracy, including 1) compiling previously published data involving intermittent rest intervals (i.e., meta-analysis); 2) experimentally collecting data on intermittent fatigue for shoulder flexion as it is not well represented in the literature; and 3) experimentally collecting data on fatigue during a dynamic task for elbow flexion as dynamic tasks have been virtually ignored in fatigue literature. The results of these investigations indicate that a mathematical model of fatigue is reasonably accurate in predicting an average fatigue response across multiple subjects for both intermittent and dynamic tasks, but does not currently reflect the often wide variation in muscle fatigue development that is observed between individuals. Accordingly, this type of modeling approach may have value for general assessments of fatigue accumulation, but will need further development and modification to better represent individual characteristics.

The development of localized muscle fatigue has classically been described by the nonlinear intensity - endurance time (ET) curve (Rohmert, 1960; El Ahrache et al., 2006). These empirical intensity-ET relationships have been well-documented and vary between joint regions. Xia and Frey Law (2008) previously proposed a three-compartment biophysical fatigue model, consisting of compartments (i.e. states) for active (MA), fatigued (MF), and resting (MR) muscle, to predict the decay and recovery of muscle force. However the model had yet to be validated for static or intermittent isometric tasks. The purpose of this thesis was to provide validation to the biophysical model. The first goal of this thesis was to determine optimal model parameter values, fatigue (F) and recovery (R), which define the "flow rate" between muscle states and to evaluate the model's accuracy for estimating expected intensity - ET curves. Using a grid-search approach with modified Monte Carlo simulations, over 1 million F and R permutations were used to predict the maximum ET for sustained isometric tasks at 9 intensities ranging from 10 - 90% of maximum in 10% increments (over 9 million simulations total). Optimal F and R values ranged from 0.00589 (Fankle) and 0.0182 (Rankle) to 0.00058 (Fshoulder) and 0.00168 (Rshoulder) , reproducing the intensity-ET curves with low mean RMS errors: shoulder (2.7s), hand/grip (5.6s), knee (6.7s), trunk (9.3s), elbow (9.9s), and ankle (11.2s). Testing the model at different task intensities (15 - 95% maximum in 10% increments) produced slightly higher errors, but largely within the 95% prediction intervals expected for the intensity-ET curves. The second goal of this thesis was to conduct a meta-analysis of available percent torque decline data as a function of duty cycle and intensity from literature. For comparison across studies, decay in MVC (% decline) was extracted at a selected range of time points: 30, 60, 90, and 120 seconds across all joints (shoulder, hand/grip, knee, trunk, elbow, and ankle). Searches of the following databases were performed: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge, and Google Scholar. The inclusion criteria included: studies with healthy human subjects, ages between 18-55 years old, intermittent tasks with force/torque data, a task time of at least 30 seconds, and published in English. Exclusion criteria included: dynamic contractions, simultaneous multi-joint testing (e.g. squat lifts), functional tasks, body/limb weight as primary resistance, and electrically stimulated contractions. The database search strategy resulted in a total of 2781 potential publications. Of these articles 44 met the required inclusion and exclusion criteria. Since there were so few publications that fit the required inclusion and exclusion criteria, static fatigue papers that were used in (Frey Law and Avin, 2010) meta-analysis and fit the inclusion requirements for this study were used to fill in points at the extreme of the surface (DC=1). Of the 194 publications that were used in the prior meta-analysis, only 3 fit the required inclusion and exclusion criteria for this analysis, for a total of 47 studies (torque decline was typically the limiting factor). From these 47 studies, empirical % decline models could be developed for the joint regions with 3 or more data points (ankle, knee, elbow, and hand/grip) and a general model for each of the 4 discrete time points. The total sample size for each joint ranged from 125 (elbow) to 306 (hand/grip). The total number of data points for each joint ranged from 28 (elbow) -to 68 (hand/grip) with a total of 193 data points extracted. The third goal of this thesis was to compare the empirical models developed from the meta-analysis to the predicted surfaces produced by the biophysical model. Each surface was compared to its empirical counterpart qualitatively and quantitatively. Qualitatively the predicted surfaces reasonable resembled the empirical models. Quantitative analysis was performed by calculating the mean RMS and relative errors between the surfaces. The predicted surfaces had reasonably low range of mean RMS errors across each time point: hand/grip (92.66-238s), knee (73.60-186.25s), elbow (23.62-96.31s), and ankle (34.02-129.63s). The quantitative analysis also showed that the percent of the data points found by the meta-analysis that fell within the predicted 95% confidence interval was reasonably high: 52%(hand/grip; 120s) to 100% (elbow; 60, 90, & 120s). This thesis concluded that this three-compartment fatigue model can be used to accurately represent joint-specific static intensity-ET curves and 3D surfaces of percent torque decline as a function of intensity and duty cycle for short intermittent tasks (i.e. <120 seconds). While the intensity-ET curves are currently used for ergonomics analysis. The relative torque decline surfaces for intermittent tasks that were developed in this thesis provide further insight into what occurs at the muscle level (i.e. decline in muscle force production) during intermittent work cycles. This insight could provide a new method for developing rest-work cycles or job rotation cycles in industry.

Four pigeons had discrimination training that required the choice of a left side-key following completion of a fixed-ratio 10 an the center key, and a right side-key response after fixed-ratio 20. Correct choices were reinforced on various fixed-interval, fixed-ratio, random-interval, and random-ratio schedules. When accuracy was examined across quarters of intervals (fixed-interval schedules) or quarters of median interreinforcerrent intervals (fixed-ratio schedules), accuracy was usually laver in the second quarter than in the first, third, or fourth quarters. When accuracy was examined across quarters of ratios (fixed-ratio schedules) or quarters of median number of correct interreinforcement trials (fixed-interval schedules), accuracy increased across quarters. These accuracy patterns did not occur m random-interval or random-ratio schedules. The results indicate that, when choice patterns differed on fixed-interval and fixed-ratio schedules, these differences were due to the methods of data analyses.

Headwater streams are extremely vulnerable to the consequences of land-use change as they are tightly coupled with the surrounding landscape. Understanding the natural processes that influence the structure and function of these ecosystems will improve our understanding of how land-use change affects them. Benthic substratum habitat was investigated in a sub-tropical headwater stream by quantifying temporal change to sediment texture of surface sediments (less than 10cm), over four years. Hydrological characteristics were also surveyed in detail, as hydrological regime is a primary determinant of sediment transportation. Additionally, measures of hydro-geological features - hydraulic conductivity and groundwater depth were made in order to explore features of sediment habitat that extend beyond the sediment-water interface. Whilst the typical discharge pattern was one of intermittent base flows and infrequent, yet extreme flood events associated with monsoonal rain patterns, the study period also encompassed a drought and a one in hundred year flood. Rainfall and discharge did not necessarily reflect the actual conditions in the stream. Surface waters were persistent long after discharge ceased. On several occasions the stream bed was completely dry. Shallow groundwater was present at variable depths throughout the study period, being absent only at the height of the drought. The sediments were mainly gravels, sand and clay. Changes in sediment composition were observed for fine particulates (size categories less than 2mm). The grain size change in the finer sediment fractions was marked over time, although bedload movement was limited to a single high discharge event. In response to a low discharge regimen (drought), sediments characteristically showed non-normal distributions and were dominated by finer materials. High-energy discharge regimes (flood) were characterised by coarsening of sands and a diminished clay fraction. Particulate organic matter from sediments showed trends of build-up and decline with the high and low discharge regimes, respectively. Benthic habitats were described according to prevailing hydro-geological parameters. Faunas from sediment substratum samples were associated with identified habitat categories. The fauna reflected the habitat variability in terms of hydrological disturbance of the substratum structure and intermittency of discharge. An applied multivariate procedure was used to correlate temporally changing environmental parameters and faunal abundance data. Faunas were correlated with a group of variables dominated by either discharge variables or sediment textural parameters. Sediment characteristics that affect substratum quality and substratum preference at the micro-scale were investigated via hypotheses testing. A model of carbon loss was used to determine how long particulate organic matter could potentially sustain microbial activity under experimental conditions. An estimate of up to 200 days was determined from this laboratory experiment. Secondly, enriched carbon isotopes were used in a field-based experiment to establish a link between sediments and macrofauna. Enrichment via organic sediments was found for various detritivorous and carnivorous taxa. In the 'third' experiment, artificial treatments were applied to elucidate substratum preference. Fauna was offered the choice of variable quantities of clay and/or quality of organic matter. There were no significant preferences found for the different substratum treatments, although further investigation is needed and a different outcome from this method may be achieved under more benign field conditions than those encountered during this experiment. Finally, the study was set within a context of the primary features of scale. Climate and hydrological features, including linkages with the alluvial aquifer and terrestrial ecosystem, and their potential to change within 'ecological time' are perceived as critical to understanding the role of benthic sediment substratum.

<p><strong>Sammanfattning</strong></p><p>Olika fälttest är flitigt använda för att utvärdera fotbollsspelares fysiska uthållighet, däribland Yo-Yo Intermittent Recovery Level 1 (Yo-Yo IR1) och Coopers löptest. Ytterst lite är dock känt om Coopertestets lämplighet som mätmetod i en sport med intermittent arbete som fotboll. Syftet med denna studie var att undersöka prestation i Coopertestet i förhållande till Yo-Yo IR1 testet hos fotbollsspelare på olika tävlingsnivåer. Under försäsongen testades 19 manliga fotbollsspelare (23 ± 4 år, 181 ± 9 cm, 77 ± 9 kg) från svensk division 1 (hög-nivå, n=5), division 3 (mellan-nivå, n=6) och division 5 (låg-nivå, n=8). Coopertestet består av oavbruten löpning så långt som möjligt under 12 minuter på löparbana. Yo-Yo IR1 testet består av upprepade 2x20 meters löpningar i ökande hastighet, med 10 sekunder aktiv vila mellan varje omgång. Testerna utfördes under standardiserade former på kvällstid med minst 72 timmars mellanrum. Resultatet för Coopertestet var; hög-nivå 3056 ± 194m, mellan-nivå 2950 ± 188m och låg-nivå 2916 ± 203m, utan signifikanta skillnader mellan grupperna (p>0,05). Yo-Yo IR1 resultaten var; hög-nivå 2264 ± 286m, mellan-nivå 1933 ± 395m och låg-nivå 1615 ± 496m. Det fanns en signifikant skillnad i testresultaten mellan hög-nivå och låg-nivå (p<0,05). Förhållandet mellan de två testerna för hela populationen var r=0,89 (p<0,001), och inom grupperna; hög-nivå r=0,69 (p=0,2), mellan-nivå r=0,99 (p<0,001) och låg-nivå r=0,98 (p<0,001). I motsats till övriga grupper visade resultaten att hög-nivå gruppen, som har större mängd fotbollsspecifik träning, inte hade något signifikant samband mellan de två testen. Coopertestets utformning med oavbruten löpning, tillsammans med dess oförmåga att särskilja mellan olika tävlingsnivåer, medför att Yo-Yo IR1 testet bör användas framför Coopertestet i syfte att få tydligare information om en fotbollsspelares fysiska uthållighet under matchsituation.</p>

Tumors need the development of new vessels from the pre-existing vasculature to bring nutrients and oxygen to the whole tumor mass. The tumor vascular network is known to be poorly functional due to architectural and functional abnormalities. The end result is an inadequate and heterogeneous tumor perfusion leading to the development of tumor hypoxia. From a therapeutic perspective, hypoxia is a source of radioresistance and the dysfunctional perfusion hampers drug delivery. Historically, tumor hypoxia refers to chronic hypoxia (or diffusion-limited hypoxia) that results from the increasing distance between O2-consuming cells and blood vessels due to the high metabolic rate of tumor cells. Many studies have demonstrated the impact of chronic hypoxia on the clonal selection of tumor cells resistant to conventional anti-cancer therapies. Growing evidence for the existence of another form of hypoxia caused by heterogeneities in tumor perfusion, namely acute or perfusion-limited hypoxia, plead however for a non-genetic source of phenotype conversion reaching not only tumor cells but also the tumor vasculature and in particular endothelial cells. In the cardiovascular field, the cyclic exposure to different pO2 levels is known to precondition cardiac myocytes to resist more prolonged ischemic insults. We hypothesized that this concept of myocardium preconditionning to promote the resistance vs pro-apoptotic stresses could be translated in tumors. Indeed, intermittent hypoxia in tumors is nothing else than cyclic changes in pO2 and radio- and chemotherapy can be viewed as pro-apoptotic stresses that the tumor can face. In particular, in the case of the tumor vasculature, the resistance could be a capacity to re-initiate angiogenesis after treatment. Radioresistance would be further potentiated since low pO2 is per se associated to reversibility of the damages. Also, since intermittent hypoxia is thought to be due in part to fluctuations in tumor blood flow (TBF), access of chemotherapy to the tumor could also further participate to chemoresistance. To address the above hypotheses, we first aimed to explore the extent and the origin of TBF fluctuations in tumor mouse models and to determine whether therapeutic modulation of such potential TBF heterogeneities could improve the efficacy of chemotherapy. We then more directly examined whether and how intermittent hypoxia could influence endothelial cell survival and modulate resistance to radiotherapy. We also took advantage of this study to dissect the molecular mechanisms driving the phenotype conversion of endothelial cells exposed to intermittent hypoxia. Finally, because VEGF plays a major role in hypoxia-mediated angiogenesis but also regulates major pro-survival pathways in endothelial cells, we evaluated the potential role of caveolin as a new therapeutic target to tackle EC resistance. Caveolin is, indeed, a key structural protein recently documented to interact with many downstream targets of VEGF. 1. To explore the extent and the origin of TBF fluctuations in tumor mouse models and to determine whether therapeutic modulation of such potential TBF heterogeneities could improve chemotherapy. We focused this part of the work on the vascular tone modulator endothelin-1. Indeed, this peptide is over-expressed in many mouse and human tumors where it is documented to act as a mitogenic factor in both para- and autocrine manners. Endothelin-1 is also a potent vasoconstrictor acting through the ETA receptors located on VSMCs. In our lab, we previously showed that over-expression of endothelin-1 in tumors accounted for the development of a myogenic tone within the tumor vasculature. We have now documented that an ETA receptor antagonist induces the relaxation of microdissected tumor arterioles and selectively and quantitatively increases tumor blood flow in experimental tumor models. We also combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. We showed that administration of an ETA receptor antagonist reduces the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provided evidence that ETA antagonist could improve the access of cyclophosphamide to the tumor compartment and thereby induces a significant tumor growth delay. 2. To examine whether and how intermittent hypoxia could influence endothelial cell survival and modulate resistance to radiotherapy. To dissect the mechanisms driving the phenotype conversion of endothelial cells exposed to intermittent hypoxia. This second part of our work, is a comprehensive investigation of the consequences of intermittent hypoxia, as caused by TBF heterogeneities, on the endothelial cell phenotype. First, we postulated that intermittent hypoxia (IH) favors endothelial cell (EC) survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We showed that exposing EC to cycles of hypoxia/re-oxygenation reduces radiation-induced cell death and promotes angiogenesis. In contrast, prolonged hypoxia failed to achieve such protection and even appeared deleterious. We also observed that although HIF-1£ is completely degraded during each re-oxygenation, its abundance is paradoxically found higher at each new hypoxic challenge. Moreover, the use of siRNA targeting HIF-1£ pointed out that HIF-1ƓÑ accumulation account for the increased resistance of EC to radiotherapy. Finally, we extended this concept in vivo by forcing IH in tumor-bearing mice and found that it is associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (vs normoxia or prolonged hypoxia). Next, we focused our work on the underlying mechanisms of EC phenotype conversion exposed to IH and particularly on potential actors that may favor HIF-1£ accumulation during IH. Prolylhydroxylases (PHD), MAPK and PI3K/Akt pathways as well as eNOS are known to regulate HIF-1£ abundance and transcriptional activity. We documented that PHD2 and PHD3 abundance are slightly decreased during IH, whereas prolonged hypoxia increases PHD3 expression in EC. We then showed that, ERK, Akt as well as eNOS were phosphorylated during reoxygenation periods of the IH protocol. We also used specific inhibitors of these cascades (i.e. PD98059, LY294002 and L-NAME, respectively), to evaluate their specific impact on HIF-1£ abundance and performed clonogenic assays to evaluate their consequences on EC survival. We showed that although, PD98059 and LY294002 sensitizes EC to pro-apoptotic stresses, only the PI3K/Akt inhibitor abrogates the HIF-1£ signal during IH. Conversely, L-NAME, a non-specific NOS-inhibitor, appears to potentiate the expression of HIF-1£ and to favor the EC survival. 3. To identify new therapeutic targets to prevent endothelial cell resistance by studying VEGF signaling, the major pro-survival and pro-angiogenic growth factor in endothelial cells. Because VEGF plays a central role in hypoxia-mediated angiogenesis and cell survival, the VEGF signaling cascade is a an obvious therapeutic target. To more specifically identify the pathways leading to cell survival and the resistance phenomena that we observed in response to intermittent hypoxia, a careful dissection of the downstream VEGF signaling cascades was performed. In this part of the work, we focused our attention on caveolin since it modulates the activity of eNOS, ERK and Akt that are major effectors acting downstream VEGF stimulation. We demonstrated the paradoxical role of caveolin-1 preventing signaling in basal conditions and ensuring the coupling between VEGFR2 and the downstream cascades upon VEGF stimulation. We used mice deficient for the caveolin-1 gene (Cav-/-) to examine the impact of caveolae suppression in a model of adaptive angiogenesis obtained after femoral artery resection. Evaluation of the ischemic tissue perfusion and histochemical analyses revealed that contrary to Cav+/+ mice, Cav-/- mice fails to recover a functional vasculature and actually loose part of the ligated limbs. We also isolated endothelial cells (ECs) from Cav-/- aorta and showed that on VEGF stimulation, endothelial tube formation is dramatically abrogated when compared with Cav +/+ ECs. The Ser1177 eNOS phosphorylation and Thr495 dephosphorylation but also the ERK phosphorylation were similarly altered in VEGF-treated Cav-/- ECs. Interestingly, caveolin transfection in Cav-/- ECs redirected the VEGFR-2 in caveolar membranes and restored the VEGF-induced ERK and eNOS activation. However, when high levels of recombinant caveolin are reached, VEGF exposure fails to activate ERK and eNOS. Altogether, these data identify caveolin as a new therapeutic target to alter VEGF signaling, in particular the cascades leading to angiogenesis and resistance to stresses.