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VEGF is essential for maintaining capillaries in mouse adult skeletal muscle. Eight-week AAV/cre-infected VEG- FLoxP(/) mice show evidence of long-term effects on skeletal muscle capillarity. Gastrocnemii from VEGFLoxP(/) transgenic mice were infected with 5 10 9 AAV/cre particles intramuscularly. Eight weeks later, infected fibers from VEG- FLoxP(/) transgenic mice were identified by nuclear immunostaining of serial cross sections with a cre recombinase antibody (green) (a) and revealed lower levels of VEGF at the myocyte periphery (green) (b), a loss of capillaries detected by alkaline phosphatase staining (purple) (c), and TUNEL-positive apoptotic cells (brown) (d). (from Tang et al., 2004).
Source publication
Long-term exposure of humans and many mammals to hypoxia leads to the activation of several cellular mechanisms within skeletal muscles that compensate for a limited availability of cellular oxygen. One of these cellular mechanisms is to increase the expression of a subset of hypoxia-inducible genes, including the expression of vascular endothelial...
Citations
... Shear stress, induced by RT, has been shown to upregulate myofiber VEGF expression in rodents through NO-mediated mechanisms (Milkiewicz et al., 2001;Baum et al., 2004). Mouse models whereby angiogenesis-related genes are knocked out, knocked down, or deleted (e.g., neuronal NOS or VEGF), demonstrate significant reduction in capillarity and/or skeletal muscle mass (Breen et al., 2008;Baum et al., 2013;Huey et al., 2016;Olfert et al., 2016). Interestingly, RT-induced muscle VEGF expression is lower in older individuals (Croley et al., 2005), and could partially explain age-related impairments in muscle capillarization in response to exercise with aging (Olsen et al., 2020). ...
Through decades of empirical data, it has become evident that resistance training (RT) can improve strength/power and skeletal muscle hypertrophy. Yet, until recently, vascular outcomes have historically been underemphasized in RT studies, which is underscored by several exercise-related reviews supporting the benefits of endurance training on vascular measures. Several lines of evidence suggest large artery diameter and blood flow velocity increase after a single bout of resistance exercise, and these events are mediated by vasoactive substances released from endothelial cells and myofibers (e.g., nitric oxide). Weeks to months of RT can also improve basal limb blood flow and arterial diameter while lowering blood pressure. Although several older investigations suggested RT reduces skeletal muscle capillary density, this is likely due to most of these studies being cross-sectional in nature. Critically, newer evidence from longitudinal studies contradicts these findings, and a growing body of mechanistic rodent and human data suggest skeletal muscle capillarity is related to mechanical overload-induced skeletal muscle hypertrophy. In this review, we will discuss methods used by our laboratories and others to assess large artery size/function and skeletal muscle capillary characteristics. Next, we will discuss data by our groups and others examining large artery and capillary responses to a single bout of resistance exercise and chronic RT paradigms. Finally, we will discuss RT-induced mechanisms associated with acute and chronic vascular outcomes.
... 17 Tissue hypoxia causes vasodilatation and the release of vascular endothelial growth factors resulting in angiogenesis. 18 Increased velocity in the blood vessel results in decreased intravascular hydrostatic pressure, which causes decreased efflux from the vessel resulting in reduced tissue oedema. The increased interstitial pressure also helps in splinting of the wound. ...
... Thus, iNPWT helps in wound healing by reducing lateral tension on the sutured wound, increasing blood flow, reducing tissue oedema and splinting. [18][19][20] The use of iNPWT has been favoured across various surgical disciplines. In a prospective multicentre RCT by Stannard et al, which included 269 fractures, the risk of SSI in the control group was 1.9 times higher than in patients treated with iNPWT. ...
Introduction:
The aim was to study the effect of incisional negative pressure wound therapy (iNPWT) in wound healing compared with standard sterile gauze dressings after major lower extremity amputation in patients with peripheral arterial disease (PAD).
Methods:
This prospective, randomised controlled trial included 50 patients undergoing major lower extremity amputations for PAD. Patients were randomised into iNPWT and standard dressing groups. The patency of blood vessels at the level of the stump was ensured with or without revascularisation. The primary outcome was wound-related complications such as surgical site infection (SSI), wound dehiscence, seroma/haematoma formation or the need for revision amputation. The secondary outcome was the time taken for the eligibility of prosthesis placement.
Results:
It was found that only 12% of the patients in the iNPWT group had SSI compared with 36% in the standard dressing group (p = 0.047). Rates of wound dehiscence, seroma/haematoma formation and revision amputation were decreased in the iNPWT group but this was not statistically significant (p > 0.05). There was a significant reduction in the time taken for eligibility of prosthesis placement in the iNPWT group (5.12 ± 1.53 vs 6.8 ± 1.95 weeks, p = 0.002).
Conclusions:
iNPWT is effective in reducing the incidence of SSI and the time taken for rehabilitation in patients undergoing major lower limb amputation due to PAD.
... The mean hospitalization time was 19.1 (17)(18)(19)(20)(21)(22)(23)(24)(25) for patients using VAC therapy and 46.2 (38-57) for patients using CWD (p=0.0001). In the evaluation made according to the initial site of the infection, the starting site was determined as genital region in 39 patients, perineal region in 12 patients, and inguinal region in four patients. ...
... This effect provides vasodilation due to nitric oxide release. [21] The classical dressing method used in treating FG in the historical process has left its place in modern methods such as hyperbaric oxygen and VAC treatment. However, the superiority of VAC therapy is controversial. ...
Objectives:
Fournier's gangrene (FG) is a rapidly progressive infection that requires emergent intervention. Wound closure is an important treatment step after surgery, and vacuum-assisted closure (VAC) can be preferred as an alternative method for wound closure. FG severity index (FGSI) scales that can be developed to evaluate the prognosis in FG. This study aims to compare VAC therapy, which was used and developed in the historical development of FG therapy, with conventional wound dressing (CWD).
Methods:
Data on who 85 patients treated at our hospital with a diagnosis of FG from January 2010 to July 2021. In the VAC group, the vacuum device was applied in a sealed manner. In the CWD group, mesh dressing was prepared. The VAC device was adjusted to subatmospheric pressure. Broad-spectrum antibiotics were administered to all patients during their follow-up. During the follow-up, as necrotic tissues were detected, redebridements were performed by providing appropriate analgesia and anesthesia. Demographic data of the patients were collected on the records. The clinical and laboratory data were obtained from the records at the 1st h, 72 h, and 1st week FSGI values were calculated. In statistical analysis, continuous variables were expressed as mean±standard deviation, ordinal variables were expressed as median [IQR], and categorical variables were expressed as n (%). In intergroup analyses, student's t-test was used if the data were normally distributed. If it did not show normal distribution, the Mann-Whitney U-test was applied.
Results:
Fifty-five patients who were diagnosed with FG were included in our study. CWD was applied to 18 patients, and VAC was applied to 37 patients. The mean 1st h FGSI of the patients who used VAC was 7.05 (3.75-8), and the patients who had CWD were 5.5 (5-9) (p=0.067). Mean 72nd-h FGSI was found to be 5.35 (3.5-7) in the VAC group and 5.33 (4.75-6.25) in the CWD group (p=0.714). The mean 1st-week FGSI VAC group was 2.97 (1-5), and in the CWD group, it was 5 (4-6) (p=0.0001).
Conclusion:
VAC significantly reduces the length of hospital stay. In our analysis, both groups observed a significant difference between the 1st-week FGSIs. This is the first study to evaluate FGSI, which is an essential predictor of the effect of VAC therapy used in treating FG. In the history of FG treatment, CWD has been replaced by VAC.
... As the initial hemoconcentration subsides, HIF-1 related upregulation of erythropoietin (EPO) sustains the increases in hemoglobin (Hb) concentration and arterial oxygen content (CaO2 = Hb x SaO2) after the first 1-2 weeks of high-altitude exposure [52]. The increase in muscle capillarity due to vascular endothelial growth factor (VEGF) up-regulation [53] represents another HIF-1-initiated response to altitude/hypoxia exposure. ...
High-altitude illnesses (HAIs) result from acute exposure to high altitude/hypoxia. Numerous molecular mechanisms affect appropriate acclimatization to hypobaric and/or normobaric hypoxia and curtail the development of HAIs. The understanding of these mechanisms is essential to optimize hypoxic acclimatization for efficient prophylaxis and treatment of HAIs. This review aims to link outcomes of molecular mechanisms to either adverse effects of acute high-altitude/hy-poxia exposure or the developing tolerance with acclimatization. After summarizing systemic physiological responses to acute high-altitude exposure, the associated acclimatization, and the epidemiology and pathophysiology of various HAIs, the article focuses on molecular adjustments and maladjustments during acute exposure and acclimatization to high altitude/hypoxia. Pivotal modifying mechanisms include molecular responses orchestrated by transcription factors, most notably hypoxia inducible factors, and reciprocal effects on mitochondrial functions and REDOX homeosta-sis. In addition, discussed are genetic factors and the resultant proteomic profiles determining these hypoxia-modifying mechanisms culminating in successful high-altitude acclimatization. Lastly, the article discusses practical considerations related to the molecular aspects of acclimatization and altitude training strategies.
... Opposite observations were made with THBS-1 gene deletion (Malek and Olfert, 2009). In adult mice, VEGF-A gene inactivation impaired exercise-induced muscle angiogenesis (Breen et al., 2008;Delavar et al., 2014;Tang et al., 2016). ...
... In addition, these in vivo studies have measured VEGF-A expression in whole skeletal muscle biopsies, which does not necessarily reflect myocyte-derived VEGF-A. Yet, myofibers represent the major source of VEGF-A production at rest and in the context of exercise-induced angiogenesis (Birot et al., 2003;Breen et al., 2008;Olfert et al., 2009;Olfert et al., 2010;Delavar et al., 2014). Only two studies have assessed the direct impact of cold stress exposure on VEGF-A expression in isolated myoblasts or myotubes (Sugasawa et al., 2016;Krapf et al., 2021). ...
... 3.2 Cold stress downregulates the level of a cleaved secreted THBS-1 fragment in the cell media but upregulates cellular THBS-1 protein in C2C12 myotubes THBS-1 and VEGF-A are respectively defined as key angiostatic and pro-angiogenic molecules in the skeletal muscle (Breen et al., 2008;Malek and Olfert, 2009;Lemieux and Birot, 2021). In the extracellular matrix, active processes cleave THBS-1 to generate bioactive THBS-1 fragments with lower molecular weights (Kessler et al., 2015). ...
The skeletal muscle tissue can adapt to exercise and environmental stressors with a remarkable plasticity. Prolonged cold stress exposure has been associated to increased skeletal muscle capillarization. Angioadaptation refers to the coordinated molecular and cellular processes that influence the remodeling of skeletal muscle microvasculature. Two cell types are central to angioadaptation: the myocytes, representing an important source of angiokines; and the skeletal muscle endothelial cell (SMECs), targets of these angiokines and main constituents of muscle capillaries. The influence of cold stress on skeletal muscle angioadaptation remains largely unknown, particularly with respect to myocyte-specific angiokines secretion or endothelial cell angioadaptive responses. Here, we use an in vitro model to investigate the impact of cold stress (28°C versus 37°C) on C2C12 myotubes and SMECs. Our main objectives were to evaluate: 1) the direct impact of cold stress on C2C12 cellular expression of angiokines and their release in the extracellular environment; 2) the indirect impact of cold stress on SMECs migration via these C2C12-derived angiokines; and 3) the direct effect of cold stress on SMECs angioadaptive responses, including migration, proliferation, and the activation of the vascular endothelial growth factor receptor-2 (VEGFR2). Cold stress reduced the secretion of angiokines in C2C12 myotubes culture media irrespective their pro-angiogenic or angiostatic nature. In SMECs, cold stress abrogated cell proliferation and reduced the activation of VEGFR2 despite a greater expression of this receptor. Finally, SMECs pre-conditioned to cold stress displayed an enhanced migratory response when migration was stimulated in rewarming conditions. Altogether our results suggest that cold stress may be overall angiostatic. However, cold stress accompanied by rewarming may be seen as a pro-angiogenic stressor for SMECs. This observation questions the potential for using pre-cooling in sport-performance or therapeutic exercise prescription to enhance skeletal muscle angioadaptive responses to exercise.
... adaptations to overcome such a constraint (Harrison 2018). For example, we know that many animals living in hypoxic environments increase the surface areas of their gas exchangers and increase the density of capillary beds (Breen et al. 2008;Sollid and Nilsson 2006). In contrast, most larger animals generally have reduced density of oxygen transport structures, matching their lower mass-specific metabolic rates, arguing against oxygen transport limitations in larger animals causing the hypometric scaling of metabolic rates (Harrison 2018 Declining body or gut surface-to-body volume ratios reduce mass-specific nutrient intake (Dynamic Energy Budget models). ...
Larger animals studied during ontogeny, across populations, or across species, usually have lower mass-specific metabolic rates than smaller animals (hypometric scaling). This pattern is usually observed regardless of physiological state (e.g. basal, resting, field, maximally-active). The scaling of metabolism is usually highly correlated with the scaling of many life history traits, behaviors, physiological variables, and cellular/molecular properties, making determination of the causation of this pattern challenging. For across-species comparisons of resting and locomoting animals (but less so for across populations or during ontogeny), the mechanisms at the physiological and cellular level are becoming clear. Lower mass-specific metabolic rates of larger species at rest are due to a) lower contents of expensive tissues (brains, liver, kidneys), and b) slower ion leak across membranes at least partially due to membrane composition, with lower ion pump ATPase activities. Lower mass-specific costs of larger species during locomotion are due to lower costs for lower-frequency muscle activity, with slower myosin and Ca++ ATPase activities, and likely more elastic energy storage. The evolutionary explanation(s) for hypometric scaling remain(s) highly controversial. One subset of evolutionary hypotheses relies on constraints on larger animals due to changes in geometry with size; for example, lower surface-to-volume ratios of exchange surfaces may constrain nutrient or heat exchange, or lower cross-sectional areas of muscles and tendons relative to body mass ratios would make larger animals more fragile without compensation. Another subset of hypotheses suggests that hypometric scaling arises from biotic interactions and correlated selection, with larger animals experiencing less selection for mass-specific growth or neurolocomotor performance. A additional third type of explanation comes from population genetics. Larger animals with their lower effective population sizes and subsequent less effective selection relative to drift may have more deleterious mutations, reducing maximal performance and metabolic rates. Resolving the evolutionary explanation for the hypometric scaling of metabolism and associated variables is a major challenge for organismal and evolutionary biology. To aid progress, we identify some variation in terminology use that has impeded cross-field conversations on scaling. We also suggest that promising directions for the field to move forward include: 1) studies examining the linkages between ontogenetic, population-level, and cross-species allometries, 2) studies linking scaling to ecological or phylogenetic context, 3) studies that consider multiple, possibly interacting hypotheses, and 4) obtaining better field data for metabolic rates and the life history correlates of metabolic rate such as lifespan, growth rate and reproduction.
... 5,6 The compression of tissue by negative pressure causes tissue hypoxia due to decreased perfusion beneath the foam which stimulates angioneogenesis and local vasodilatation due to release of nitric oxide. [7][8][9] There is a controversy regarding the optimal pressure application for VAC dressing. The animal model study showed increased granulation tissue formation with 125 mmHg vacuum compared with low (25 mmHg) or high (500 mmHg) vacuum suction. ...
Background: Low-cost vacuum-assisted closure (VAC) can be used as an alternative method for wound management. Objectives: To observe the effectiveness of low-cost vacuum-assisted closure dressing in wound management. Methods: A descriptive cross-sectional hospital-based study was conducted in the Department of Plastic Surgery, Kathmandu Medical College from April 2021 to February 2022 to observe age, sex, indication, type of wound with history of comorbidities, number of dressings, duration of hospital stays, and complications like: bleeding, haematoma, and delay in wound healing . Results: A total of 22 patients were included by convenience sampling technique in the study with 21 (95.5%) acute and one (4.5%) case of chronic wound with ulcer. The mean age was 39 ± 18.157 years ranging from 13-76 years. Most of them were males (15, 68.2%). The mean duration of wound presentation was 5.45 ± 9.127 days ranging from 1-45 days. The mean duration of hospitalisation was 20.45 ± 11.467 days ranging from 5-45 days. Eight (36.4%) patients were with comorbidities like Diabetes Mellitus, Hypertension, Peripheral vascular diseases etc., and no mortality was recorded. Conclusion: Low-cost Vacuum-assisted closure is a very easy and efficient alternative method for wound care.
... In the context of an inflammatory milieu with cachexia, the understudied role of muscular capillarization is of particular interest, as the combination of local muscular inflammation and fiber atrophy has also been reported for chronic hypoxic exposure [69,70]. Increases in capillary density with chronic hypoxia are mainly attributable to fiber atrophy, however, they obviously require increased local VEGF expression which contributes to unchanged capillary-to-fiber-ratio. ...
Skeletal muscle wasting critically impairs the survival and quality of life in patients with pancreatic ductal adenocarcinoma (PDAC). To identify the local factors initiating muscle wasting, we studied inflammation, fiber cross-sectional area (CSA), composition, amino acid metabolism and capillarization, as well as the integrity of neuromuscular junctions (NMJ, pre-/postsynaptic co-staining) and mitochondria (electron microscopy) in the hindlimb muscle of LSL-KrasG12D/+; LSL-TrP53R172H/+; Pdx1-Cre mice with intraepithelial-neoplasia (PanIN) 1-3 and PDAC, compared to wild-type mice (WT). Significant decreases in fiber CSA occurred with PDAC but not with PanIN 1-3, compared to WT: These were found in the gastrocnemius (type 2x: −20.0%) and soleus (type 2a: −21.0%, type 1: −14.2%) muscle with accentuation in the male soleus (type 2a: −24.8%, type 1: −17.4%) and female gastrocnemius muscle (−29.6%). Significantly higher densities of endomysial CD68+- and cyclooxygenase-2+ (COX2+) cells were detected in mice with PDAC, compared to WT mice. Surprisingly, CD68+- and COX2+-cell densities were also higher in mice with PanIN 1-3 in both muscles. Significant positive correlations existed between muscular and hepatic CD68+- or COX2+ cell densities. Moreover, in the gastrocnemius muscle, suppressor-of-cytokine-3 (SOCS3) expressions was upregulated >2.7-fold with PanIN 1A-3 and PDAC. The intracellular pools of proteinogenic amino acids and glutathione significantly increased with PanIN 1A-3 compared to WT. Capillarization, NMJ, and mitochondrial ultrastructure remained unchanged with PanIN or PDAC. In conclusion, the onset of fiber atrophy coincides with the manifestation of PDAC and high-grade local (and hepatic) inflammatory infiltration without compromised microcirculation, innervation or mitochondria. Surprisingly, muscular and hepatic inflammation, SOCS3 upregulation and (proteolytic) increases in free amino acids and glutathione were already detectable in mice with precancerous PanINs. Studies of initial local triggers and defense mechanisms regarding cachexia are warranted for targeted anti-inflammatory prevention.
... Гипоксия -важная движущая сила ангиогенеза раны. Экспрессия гена HIF-1α из-за гипоксического градиента между зоной образующейся грануляционной ткани и васкуляризированным микроокружением запускает продукцию фактора роста эндотелия сосудов (VEGF) [38]. Первоначально находящиеся в состоянии покоя резидентные эндотелиальные клетки активируются несколькими ангиогенными факторами, включая фактор роста фибробластов, VEGF, фактор роста тромбоцитов (PDGF), ангиогенин и трансформирующие факторы роста α и β (TGF-α и TGF-β). ...
Currently, there is no consensus among scientists on the place of scar tissue and, in particular, granulation tissue in the classification of fibrous connective tissue. This paper aimed to generalize literature data on the structure and development of fibrous scar tissue. It is demonstrated that granulation tissue is mostly composed of myofibroblasts, along with fibroblasts, as well as old fibroblasts, endothelial cells, and immune cells. Myofibroblasts are characterized by a developed cytoskeleton represented by stress fibers, which ensures active migration of these cells and remodelling of the surrounding intercellular substance. The developed synthetic apparatus of the myofibroblast, in addition to synthesis of the intercellular substance, provides cell paracrine activity, which maintains the homeostasis of the cellular components of granulation tissue. The intercellular substance is represented by type III collagen fibers; elastic fibers are absent. The ground substance has a high degree of hydration and low stiffness and is rich in glycosaminoglycans, collagenases and fibronectin; this greatly facilitates the migration of myofibroblasts, endotheliocytes and fibrocytes. The ability of the intercellular substance to accumulate growth factors plays an important role in the transdifferentiation of fibrocytes into myofibroblasts. The blood vessels of the granulation tissue are the source of fibrocytes, which play a key role in the formation of granules of the newly formed tissue around the vessel. Myofibroblast apoptosis triggers the differentiation of granulation tissue into dense fibrous loose connective tissue. At the same time, type III collagen is replaced by type I collagen, elastin fibers appear, angiogenesis is inhibited, and mechanisms providing sympathetic innervation of connective tissue are triggered. Thus, granulation tissue can be considered as temporary connective tissue, which is one of the examples of dedifferentiation that occurs not only at the cellular, but also at the tissue level.
... In addition to the molecular responses that may prompt glycolytic and mitochondrial adaptations following RSH, we also show that RSH increased VEGFA mRNA, which is a hallmark of HIF-1 signaling (Liu et al. 1995;Forsythe et al. 1996). Hypoxia and hypoxia + EPS also increased VEGFA mRNA in a HIF-1-dependent manner in vitro, further supporting its role in signaling for exercise and hypoxia-induced angiogenesis (Tang et al. 2004;Breen et al. 2008). In regard to RSH, this HIF-1-dependent increase in VEGFA may stimulate skeletal muscle capillarization and thus muscle perfusion. ...
Purpose
Our aim was to determine the effect of repeated sprint exercise in hypoxia on HIF-1 and HIF-1-regulated genes involved in glycolysis, mitochondrial turnover and oxygen transport. We also determined whether genes upregulated by exercise in hypoxia were dependent on the activation of HIF-1 in an in vitro model of exercise in hypoxia.
Methods
Eight endurance athletes performed bouts of repeated sprint exercise in control and hypoxic conditions. Skeletal muscle was sampled pre, post and 3 h post-exercise. HIF-1α protein and HIF1A, PDK1, GLUT4, VEGFA, BNIP3, PINK1 and PGC1A mRNA were measured. C2C12 myotubes were exposed to hypoxia and muscle contraction following treatment with a HIF-1α inhibitor to determine whether hypoxia-sensitive gene expression was dependent on HIF-1α.
Results
Sprint exercise in hypoxia increased HIF-1α protein expression immediately post-exercise [fold change (FC) = 3.5 ± 2.0]. Gene expression of PDK1 (FC = 2.1 ± 1.2), BNIP3 (FC = 2.4 ± 1.4) and VEGFA (FC = 2.7 ± 1.7) increased 3 h post-exercise in hypoxia but not control. PGC1A mRNA increased 3 h post-exercise in control (FC = 5.16) and hypoxia (FC = 5.7 ± 4.1) but there was no difference between the trials. Results from the in vitro experiment showed that hypoxia plus contraction also increased PDK1, BNIP3, and VEGFA gene expression. These responses were inhibited when HIF-1 protein activity was suppressed.
Conclusion
Repeated sprint exercise in hypoxia upregulates some genes involved in glycolytic metabolism, mitochondrial turnover, and oxygen transport. HIF-1α is necessary for the expression of these genes in skeletal muscle cells.
