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Modifications of microvascular filtration capacity in human limbs by training and electrical stimulation.

This study investigated whether an increase in microvascular surface area as a result of endurance training, which increases human skeletal muscle capillarity, would translate to greater capacity for fluid filtration compared with strength training, which does not affect capillary supply. Values for filtration capacity, Kf, derived from the slope of calf volume change, Jv, measured by venous occlusion plethysmography, against cuff pressure during a protocol of small cumulative pressure steps, were significantly higher in endurance athletes (5.78 +/- 0.88 mL min(-1) 100 mL(-1) mmHg(-1) x 10(-3), P < 0.05) than controls (3.38 +/- 0.32 mL min(-1) 100 mL(-1) mmHg(-1) x 10(-3) whereas strength-trained athletes had values similar to control (4.08 +/- 0.56 mL min(-1) 100 mL(-1) mmHg(-1) x 10(-3), ns), suggesting that surface area is important. However, when sedentary subjects underwent either a 4-week unilateral dynamic plantarflexion training programme (70% peak power, 20 min day(-1), 5 days week(-1) or a calf muscle electrical stimulation programme (8 Hz, 3 x 20 min day(-1), 5 days week(-1), neither of which caused limb blood flow to alter after training nor would be expected to increase capillarity, only the stimulation group showed a significant increase in Kf (6.68 +/- 0.62 mL min(-1) 100 mL(-1) mmHg(-1) x 10(-3) post-training vs. 3.38 +/- 0.38 pre-training, P < 0.05). This may be because stimulation enhances perfusion preferentially to glycolytic fibres, or maintains high levels of vascular endothelial growth factor (VEGF) or changes lymph clearance.

Adaptation, Physiological↗

The biology of VEGF and its receptors.

Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

Animals↗

A study of physiologic angiogenesis in the human using the dental pulp as an in vivo model.

With the commonly used in vivo animal models of angiogenesis, direct extrapolation of results to the human is not possible. The results presented from this study exemplify various phases of angiogenesis, from cell migration to apoptosis. This supports the use of the dental pulp of the developing human tooth as a viable model of in vivo physiologic angiogenesis.

Apoptosis↗

Ovariectomy improves neovascularization and microcirculation of freely transplanted ovarian follicles.

To investigate the influence of ovariectomy on the physiological process of neovascularization of ovarian follicles, we harvested follicles with a theca interna at 48 h after pregnant mare's serum gonadotropin (PMSG) treatment of Syrian golden hamsters, for subsequent transplantation onto striated muscle tissue of chronically implanted skinfold chambers of non-ovariectomized PMSG-synchronized hamsters and bilaterally ovariectomized hamsters. Non-ovariectomized non-PMSG-treated animals served as controls. During a 2 week period after transplantation, neovascularization of these freely transplanted grafts was quantified in vivo by assessment of the newly developed microvascular follicular network, its microvessel density, the diameter of microvessels and their volumetric blood flow using fluorescence microscopic techniques. At day 3 after transplantation, capillary sprouts could be observed in all groups studied, finally developing a complete glomerulum-like microvascular network within 5-10 days. In ovariectomized animals, however, vascularization of follicular tissue was found to be accelerated and enhanced when compared with the follicles in both groups of non-ovariectomized animals. This was associated with significantly higher capillary blood perfusion, which may in part represent the graft's adaptive response to pro-angiogenic stimuli due to elevated gonadotropin levels, but might in particular be mediated by gonadotropin-induced release of vasoactive substances. Interestingly, small preantral follicles lacking a theca interna failed to vascularize in either of the groups. In conclusion, the study demonstrates that ovariectomy improves neovascularization and microcirculation of freely transplanted ovarian follicles.

Analysis of Variance↗

Cardiovascular genomics: a current overview of in vivo and in vitro studies.

The cardiovascular system is the first system that is developed in the embryo. The cardiovascular development is a complex process involving the coordination, differentiation, and interaction of distinct cell lineages to form the heart and the diverse array of arteries, veins, and capillaries required to supply oxygen and nutrients to all tissues. Embryonic stem cells have been proposed as an interesting model system to investigate molecular and cellular mechanisms involved in mammalian development. The present review is focused on extrinsic soluble factors, intrinsic transcription factors, receptors, signal transduction pathways, and genes regulating the development of cardiovascular system in vivo and in vitro. Special emphasis has been given to cardiovascular genomics including gene expression studies on the cardiovascular system under developmental and pathophysiological conditions.

Animals↗

Therapeutic angiogenesis: translating experimental concepts to medically relevant goals.

Angiogenesis is central to many physiological and pathological phenomena. In physiological angiogenesis, new vessels are well shaped and their growth is finely tuned to match the metabolic needs of tributary tissues. Accordingly, neovascularization is activated by physical exercise and destabilized by non-use. In contrast, pathological blood vessels that are observed in retinal neovascularization, cancer or in ischemic tissues are leaky, irregularly shaped, and tend to form arterial-venous fistulae. A great deal of attention is focused on new approaches for medical manipulation of vascular growth. These methods are aimed at facilitating the reperfusion of ischemic tissues or eradicating pathological vasculature. In this position paper, we challenge the rationale of therapeutic angiogenesis for the cure of myocardial and peripheral ischemia. Therapeutic angiogenesis aims at combating the insufficiency of, or insensitivity to angiogenic factors in the setting of atherosclerotic-induced arterial occlusion. However, clinical evidence indicates that such a defect is not common among patients with ischemic disease, as a whole. Genetic and environmental factors could account for the great heterogeneity in the expression of the master angiogenic factors. Future improvements in the strategy would require the introduction of in vitro assays and in vivo imaging systems for assessing human angiogenesis. Finally, the promise is to find individualized angiogenesis-based therapies for a genuine cure of ischemia and prevention of organ failure.

Angiogenesis Inducing Agents↗

Changes in fetal capillaries during preplacental hypoxia: growth, shape remodelling and villous capillarization in placentae from high-altitude pregnancies.

Patterns of fetoplacental angiogenesis and villous growth vary in pregnancies complicated by different forms of fetal hypoxia. This study uses stereological estimators to examine absolute and relative dimensions of villi and fetal capillaries in cases of preplacental hypoxia due to pregnancy at high altitude. Placental samples were drawn from well-defined subjects in different ethnic groups born, raised and completing term pregnancies at low (500 m) and high altitude (3600 m above sea level). Volumes, surfaces and lengths were used to monitor the nett growth of villi and capillaries. Indices of villous capillarization comprised volume, surface and length densities and capillary:villus surface and length ratios. Villus/capillary 'calibre' and shape were quantified using cross-sectional areas, perimeters and shape coefficients (perimeter(2)/area). Group comparisons were drawn by two-way analyses of variance with altitude and ethnicity as the main factors. Volumes, surfaces and lengths of villi, and volumes of capillaries, were reduced at high altitude. Capillary volume declined primarily by formation of narrower microvessels which were more irregular in outline. There were no differences in capillary surface area or length. Cross-sectional sizes and shapes of villi were unaltered. Differences in villous capillarization were confined to higher surface and length densities. Ethnic differences in villous length, capillary length and cross-sectional area tended to favour native groups who are pre-adapted to life at high altitude. Results show that high-altitude pregnancy is not accompanied by increased angiogenesis but may involve enhanced villous capillarization and vascular shape remodelling. Comparisons are drawn with changes seen in maternal anaemia. It is concluded that absolute and relative measures of villous and capillary growth are required lest misinterpretations are introduced by equating hypercapillarization with enhanced angiogenesis or the pattern of capillary branching. The importance of controlling for various potential confounders is also emphasized.

Adaptation, Physiological↗

Pigment epithelium-derived factor: a potent inhibitor of angiogenesis.

In the absence of disease, the vasculature of the mammalian eye is quiescent, in part because of the action of angiogenic inhibitors that prevent vessels from invading the cornea and vitreous. Here, an inhibitor responsible for the avascularity of these ocular compartments is identified as pigment epithelium-derived factor (PEDF), a protein previously shown to have neurotrophic activity. The amount of inhibitory PEDF produced by retinal cells was positively correlated with oxygen concentrations, suggesting that its loss plays a permissive role in ischemia-driven retinal neovascularization. These results suggest that PEDF may be of therapeutic use, especially in retinopathies where pathological neovascularization compromises vision and leads to blindness.

Animals↗

Cell-matrix interactions, alterations with aging, involvement in angiogenesis.

Cell-matrix interactions are mediated primarily by integrins, which are membrane-spanning receptors capable of cell or matrix component recognition and involved in two-way intracellular signal transduction. Aging is associated with quantitative and qualitative changes in matrix macromolecules and the integrins that bind them. These changes translate into alterations in cell-matrix interactions. Integrin expression modifications have also been reported in some diseases.

Aging↗

Functional and molecular MR imaging of angiogenesis: seeing the target, seeing it work.

Intensive research over the last years led to the discovery of multiple molecular pathways and intricate regulatory network controlling the growth and regression of blood vessels in general and angiogenesis in particular. The difficulties in elucidation of the regulation of angiogenesis, stems from the inherent complexity due to participation of many cell types, under a dominant impact of physiological and environmental effects of flow, perfusion, and oxygenation. Major advances were achieved with the use of sophisticated transgenic mice models engineered so as to provide spatially and temporally controlled expression of specific factors alone or in combination. In vivo analysis of these models frequently requires the use of non-invasive imaging modalities for measurement of functional parameters of the vasculature along with dynamic molecular information. Optical methods are extensively applied for the study of angiogenesis [Brown et al., 2001] but provide very limited tissue penetration. MRI offers the advantage of being non-invasive with uniform and relatively high spatial resolution for deep tissues. Multiple MRI approaches for monitoring angiogenesis were developed over the last years, each looking at a particular step in the process. The aim of this paper is to analyze the clinical, pharmaceutical, and biological needs for imaging of angiogenesis, and to critically evaluate the strengths and weaknesses of functional and molecular imaging for monitoring angiogenesis. The inherent problem of validation of different measures of angiogenesis, and the advantages and limitations associated with application of MRI based methods, as surrogates for other measurements of angiogenesis will be discussed. The terms molecular imaging and functional imaging are frequently loosely defined with a significant overlap between the two. For the sake of this paper we will apply a narrower definition of both terms, where molecular imaging will apply to methods directed towards detection of specific biological molecules that participate directly in (regulation of) a physiological process; while functional imaging will be used to describe those methods that aim to detect the physiological response to a defined (molecular) stimulus.

Animals↗

Peroxisome proliferator-activated receptors (PPARs) and ovarian function--implications for regulating steroidogenesis, differentiation, and tissue remodeling.

The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors involved in varied and diverse processes such as steroidogenesis, angiogenesis, tissue remodeling, cell cycle, apoptosis, and lipid metabolism. These processes are critical for normal ovarian function, and all three PPAR family members--alpha, delta, and gamma, are expressed in the ovary. Most notably, the expression of PPARgamma is limited primarily to granulosa cells in developing follicles, and is regulated by luteinizing hormone (LH). Although much has been learned about the PPARs since their initial discovery, very little is known regarding their function in ovarian tissue. This review highlights what is known about the roles of PPARs in ovarian cells, and discusses potential mechanisms by which PPARs could influence ovarian function. Because PPARs are activated by drugs currently in clinical use (fibrates and thiazolidinediones), it is important to understand their role in the ovary, and how manipulation of their activity may impact ovarian physiology as well as ovarian pathology.

Animals↗

[Fibroblast growth factor-2].

Fibroblast growth factor-2 is a member of a large family of proteins that bind heparin and heparan sulfate and modulate the function of a wide range of cell types. FGF-2 occurs in several isoforms resulting from alternative initiations of traslation: an 18 kDa cytoplasmic isoform and four larger molecular weight nuclear isoforms (22, 22.5, 24 and 34 kDa). It acts mainly through a paracrine/autocrine mechanism involving high affinity transmembrane receptors and heparan sulfate proteoglycan low affinity receptors. It is expressed mostly in tissues of mesoderm and neuroectoderm origin, and plays an important role in mesoderm induction, stimulates the growth and development of the new blood vessels (angiogenesis), normal wound healing and tissue development. FGF-2 positively regulates hematopoiesis by acting on various cellular targets: stromal cells, early and committed hematopoietic progenitors and possibly some mature blood cells. FGF-2 is a potent hematopoietic growth factor that is likely to play an important role in physiological and pathological hematopoiesis.

Animals↗

Exercise has a positive effect on endothelial progenitor cells, which could be necessary for vascular adaptation processes.

Since many years, it was believed that the sole mechanism for postnatal growth of new blood vessels in response to exercise is angiogenesis, occurring through vascular sprouting and intucesseption. Today, accumulating evidence indicates that peripheral blood contains marrow-derived endothelial progenitor cells, which have the potential to differentiate into mature endothelial cells and which can contribute to postnatal vessel growth and repair (postnatal vasculogenesis). However, controversy exists with respect to the identification and the origin of endothelial progenitor cells, this review focus on the different possible sources of endothelial progenitor cells like hematopoietic stem cells, monocytes/macrophages, and mesenchymal stem cells (multipotent adult progenitor cells; MAPCs). In the last years, several groups were able to show the positive effects of exercise on endothelial progenitor cells, which means that vasculogenesis/endothelial progenitor cells might as well contribute to the growth of new blood vessels in adaptation processes. The effect of exercise on endothelial progenitor cells and possible mobilization-factors like hypoxia are discussed.

Adaptation, Physiological↗

What makes vessels grow with exercise training?

Exercise and muscle contractions create a powerful stimulus for structural remodeling of the vasculature. An increase in flow velocity through a vessel increases shear stress, a major stimulus for enlargement of conduit vessels. This leads to an endothelial-dependent, nitric oxide-dependent enlargement of the vessel. Increased flow within muscle, in the absence of contractions, leads to an enhanced capillarity by intussusceptive angiogenesis, a process of capillary splitting by intraluminal longitudinal divide. In contrast, sprouting angiogenesis requires extensive endothelial cell proliferation, with degradation of the extracellular matrix to permit migration and tube formation. This occurs during muscle adaptations to chronic contractions and/or muscle overload. The angiogenic growth factor VEGF appears to be an important element in angiogenesis. Recent advances in research have identified hemodynamic and mechanical stimuli that upregulate angiogenic processes, demonstrated a complexity of potent growth factors and interactions with their corresponding receptors, detected an interaction of cellular signaling events, and identified important tissue reorganization processes that must be coordinated to effect vascular remodeling. It is likely that much of this information is applicable to the vascular remodeling that occurs in response to exercise and/or muscle contractions.

Adaptation, Physiological↗

Antimicrobial peptides: current status and therapeutic potential.

Antimicrobial peptides (AMPs) are effector molecules of the innate immune system. A variety of AMPs have been isolated from species of all kingdoms and are classified based on their structure and amino acid motifs. AMPs have a broad antimicrobial spectrum and lyse microbial cells by interaction with biomembranes. Besides their direct antimicrobial function, they have multiple roles as mediators of inflammation with impact on epithelial and inflammatory cells influencing diverse processes such as cell proliferation, immune induction, wound healing, cytokine release, chemotaxis and protease-antiprotease balance. AMPs qualify as prototypes of innovative drugs that may be used as antimicrobials, anti-lipopolysaccharide drugs or modifiers of inflammation. Several strategies have been followed to identify lead candidates for drug development, to modify the peptides' structures, and to produce sufficient amounts for pre-clinical and clinical studies. This review summarises the current knowledge about the basic and applied biology of AMPs.

Animals↗