Capillary Regression Research Articles

Tipping the balance from angiogenesis to fibrosis in CKD

Chronic progressive renal fibrosis leads to end-stage renal failure many patients with chronic kidney disease (CKD). Loss of the rich peritubular capillary network is a prominent feature, and seems independent of the specific underlying disease. The mechanisms that contribute to peritubular capillary regression include the loss of glomerular perfusion, as flow-dependent shear forces are required to provide the survival signal for endothelial cells. Also, reduced endothelial cell survival signals from sclerotic glomeruli and atrophic or injured tubule epithelial cells contribute to peritubular capillary regression. In response to direct tubular epithelial cell injury, and the inflammatory reaction that ensues, capillary pericytes dissociate from their blood vessels, also reducing endothelial cell survival. In addition, direct inflammatory injury of capillary endothelial cells, for instance in chronic allograft nephropathy, also contributes to capillary dropout. Chronic tissue hypoxia, which ensues from the rarefaction of the peritubular capillary network, can generate both an angiogenic and a fibrogenic response. However, in CKD, the balance is strongly tipped toward fibrogenesis. Understanding the underlying mechanisms for failed angiogenesis in CKD and harnessing endothelial-specific survival and pro-angiogenic mechanisms for therapy should be our goal if we are to reduce the disease burden from CKD.

Regression of retinal capillaries following N‐methyl‐D‐aspartate‐induced neurotoxicity in the neonatal rat retina

Degeneration of retinal capillaries occurs following N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity, and the degree of capillary degeneration decreases in an age-dependent manner. To determine the role of vascular endothelial growth factor (VEGF) in the high susceptibility of capillaries to neuronal damage during the early postnatal stage, this study compares the vascular regression patterns between NMDA-treated retinas and retinas treated with N-[2-chloro-4-{(6,7-dimethoxy-4-quinazolinyl)oxy}phenyl]-N'-propylurea (KRN633), a VEGF receptor tyrosine kinase inhibitor, in neonatal rats. Two days after a single intravitreal injection of NMDA (200 nmol/eye) on postnatal day (P) 7, substantial retinal neuron loss and delayed expansion of the retinal vascular bed were observed. The reduction in the capillary density in the central retina reached statistical significance 4 days after NMDA treatment. In retinas of rats injected subcutaneously with KRN633 (10 mg/kg) on P7 and P8, simplified vasculature attributable to capillary regression and prevention of endothelial cell growth were seen on P9, whereas no visible changes in the morphology of the retinal layers were observed. The degree of capillary degeneration in NMDA-treated retinas was less than that in KRN633-treated retinas. No apparent changes in immunoreactivities for VEGF were found 2 days after NMDA treatment. These results indicate that neuronal cell loss in the retina precedes retinal capillary degeneration following NMDA treatment, and VEGF-dependent immature capillaries might be more susceptible to NMDA-induced neuronal damage.

Effects of detraining on the temporal expression of positive and negative angioregulatory proteins in skeletal muscle of mice.

Temporal expression of positive and negative angiogenic factors in response to detraining is poorly understood. We report the protein expression of anti-angiogenic peptides (thrombospondin-1, TSP-1; and endostatin) as well as pro-angiogenic factors (vascular endothelial growth factor, VEGF; matrix metalloproteinases-2 and -9), and nucleolin (a nuclear protein involved with synthesis and maturation of ribosomes) in response to detraining in triceps surae muscles of C57BL/6 mice. Male mice were allowed to exercise voluntarily for 21days, and then basal and acute response to exercise were evaluated at 1, 7, 14 and 28days detraining (D1, D7, D14, D28, respectively, n=12/group). As seen in the D1 mice, training resulted in the increased muscle capillary-to-fibre ratio (C/F), increased maximal running time and elevated basal expression of VEGF and matrix metalloproteinase-9 (P<0.05). After 7days of detraining (D7), C/F levels were similar to control levels, but both basal VEGF and TSP-1 were elevated (P<0.05). At D14 and D28, TSP-1 protein was not different compared to baseline levels; however, VEGF was elevated in gastrocnemius (GA), but not the soleus (SOL) or plantaris (PLT) muscles, of D14 mice. Endostatin tended to decrease in D14 and D28 compared to controls. Timing of nucleolin protein expression differed between muscle groups, with increases at D1, D7 and D14 in the PLT, SOL and GA muscles, respectively. The response of VEGF and nucleolin to acute exercise was blunted with training, and remained blunted in the PLT and SOL even after 28days of detraining, at a time point long after muscle capillarization was observed to be similar to pre-training levels. These data suggest that TSP-1 may be a mediator of capillary regression with detraining, even in the face of elevated VEGF, suggesting that pro-angiogenic regulators may not be able to prevent the regression of skeletal muscle capillaries under physiological conditions. The responses of matrix metalloproteinases, endostatin and nucleolin poorly correlated with detraining-induced capillary regression.

Amelioration of capillary regression and atrophy of the soleus muscle in hindlimb-unloaded rats by astaxanthin supplementation and intermittent loading.

A chronic decrease in neuromuscular activity (activation and/or loading) results in muscle atrophy and capillary regression that are due, in part, to the overproduction of reactive oxygen species. We have reported that antioxidant treatment with astaxanthin attenuates the overexpression of reactive oxygen species in atrophied muscles that, in turn, ameliorates capillary regression in hindlimb-unloaded rats. Astaxanthin supplementation, however, had little effect on muscle mass and fibre cross-sectional area. In contrast, intermittent loading of the hindlimbs of hindlimb-unloaded rats ameliorates muscle atrophy. Therefore, we hypothesized that the combination of astaxanthin supplementation and intermittent loading would attenuate both muscle atrophy and capillary regression during hindlimb unloading. As expected, 2 weeks of hindlimb unloading resulted in atrophy, a decrease in capillary volume and a shift towards smaller-diameter capillaries in the soleus muscle. Intermittent loading alone (1 h of cage ambulation per day) attenuated atrophy of the soleus, while astaxanthin treatment alone maintained the capillary network to near control levels. The combination of intermittent loading and astaxanthin treatment, however, ameliorated atrophy of the soleus and maintained the capillary volume and luminal diameters and the superoxide dismutase-1 protein levels near control values. These results indicate that intermittent loading combined with astaxanthin supplementation could be an effective therapy for both the muscle atrophy and the capillary regression associated with a chronic decrease in neuromuscular activity.

HIF-1α/COX-2 expression and mouse brain capillary remodeling during prolonged moderate hypoxia and subsequent re-oxygenation

Dynamic microvascular remodeling maintains an optimal continuous supply of oxygen and nutrients to the brain to account for prolonged environmental variations. The objective of this study was to determine the relative time course of capillary regression during re-oxygenation after exposure to prolonged moderate hypoxia and expression of the primary signaling factors involved in the process. Four-month old male C57BL/6 mice were housed and maintained in a hypobaric chamber at 290Torr (0.4atm) for 21 days and allowed to recover at normoxia (room air) for up to 21 days. The mice were either decapitated or perfused in-situ and brain samples collected were either homogenized for Western blot analysis or fixed and embedded in paraffin for immunohistochemistry. Hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and erythropoietin (EPO) expression were increased during hypoxic exposure and diminished during subsequent re-oxygenation. However, cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2) were both elevated during hypoxia as well as subsequent re-oxygenation. Significantly increased capillary density at the end of the 3rd week of hypoxia regressed back toward normoxic baseline as the duration of re-oxygenation continued. In conclusion, elevated COX-2 and Ang-2 expression during hypoxia where angiogenesis occurs and re-oxygenation, when micro-vessels regress, identifies these proteins as vascular remodeling molecules crucial for angioplasticity.

Thyroid Hormone Inactivation in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib.1 The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism.2 Multiple mechanisms of this effect have been proposed, including decreased iodine organification3 and glandular capillary regression.4 Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone–inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.

Nucleoprotein supplementation combined with intermittent loading prevents capillary regression induced by hindlimb unloading in rat soleus muscle (LB810)

Amino acids supplementation and exercise have been shown to promote physical activity‐induced angiogenesis. Therefore, the aim of this study was to determine the effects of nucleoprotein, which was composed of wide variety of amino acids, supplementation combined with intermittent loading on the capillary regression. Hindlimb unloading resulted in decrease of capillary‐to‐fiber (C/F) ratio and citrate synthase (CS) activity in the soleus muscle. Intermittent loading could not prevent the decrease in C/F ratio and CS activity, whereas nucleoprotein supplementation combined with intermittent loading could prevent the decrease in C/F ratio and CS activity in the soleus muscle. In addition, disuse‐associated changes in kinase insert domain receptor (KDR), a pro‐angiogenesis factor, and thrombospondin‐1 (TSP‐1), an anti‐angiogenesis factor, were prevented by nucleoprotein supplementation combined with intermittent loading. These results indicate that nucleoprotein supplementation combined with intermittent loading is effective to prevent capillary regression, maintaining oxidative enzyme activity and the balance between pro‐ and anti‐angiogenesis factors. Supported by Grants‐in‐Aid for Science Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the internal funds of Nissan Chemical Industries, Ltd.

Multiple Wall In-folds Sub-divide Single Segments During Capillary Regression in Hyperoxic Acute Lung Injury

The present study provides further insight into the structural processes that remodel pulmonary capillaries in the injured adult lung. Early in hyperoxia acute lung injury (HALI), many sub-dividing segments are present throughout the capillary network before segment occlusion and loss predominate and capillary density decreases later in the period. A second segment sub-division triggered in regenerating capillaries after air breathing (post-HALI) demonstrates a similar mechanism of organization at a time of contrasting change in the capillary density. As we have previously reported, the process of segment sub-division includes in-folding of the endothelial-epithelial surface (alveolar–capillary membrane) to form inter-luminal structures (ILSs) and loops, with loop separation increasing segment number. Unexpectedly, the findings support remodeling of the capillary density by wall in-folding in acute lung injury, demonstrating a similar mechanism in capillary regression as well as in regeneration in the adult lung.

Risks associated with sunitinib use and monitoring to improve patient outcomes

Risks associated with sunitinib use and monitoring to improve patient outcomes

Preventive effect of nucleoprotein on hindlimb unloading-induced capillary regression in rat soleus muscle

We investigated the preventive effects of nucleoprotein on capillary regression and mitochondrial dysfunction induced by unloading in the soleus muscle of rats. Nucleoprotein is a supplement made from soft roe of salmon, and its major components are nucleotides and protamine. Adult male Sprague-Dawley rats were divided randomly into control, hindlimb unloading (HU), and hindlimb unloading plus nucleoprotein administration (HU+ NP) groups. Hindlimb unloading was carried out for 2 weeks in the rats belonging to the HU and the HU+ NP groups. The rats of the HU+ NP group were administered nucleoprotein (500 mg/kg) using a feeding needle twice a day for 2 weeks. Hindlimb unloading resulted in capillary regression, decreased succinate dehydrogenase activity of the muscle fiber, and decreased PGC-1α expression in the soleus muscle. These effects were prevented by administration of nucleoprotein. Nucleoprotein appears to prevent capillary regression and mitochondrial dysfunction caused by unloading of the skeletal muscle. Therefore, nucleoprotein supplementation may be an effective therapy for maintaining capillary network and mitochondrial metabolism of the muscle fiber during an unloading period.

Effects of Pleiotrophin Overexpression on Mouse Skeletal Muscles in Normal Loading and in Actual and Simulated Microgravity

Pleiotrophin (PTN) is a widespread cytokine involved in bone formation, neurite outgrowth, and angiogenesis. In skeletal muscle, PTN is upregulated during myogenesis, post-synaptic induction, and regeneration after crushing, but little is known regarding its effects on muscle function. Here, we describe the effects of PTN on the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles in mice over-expressing PTN under the control of a bone promoter. The mice were maintained in normal loading or disuse condition, induced by hindlimb unloading (HU) for 14 days. Effects of exposition to near-zero gravity during a 3-months spaceflight (SF) into the Mice Drawer System are also reported. In normal loading, PTN overexpression had no effect on muscle fiber cross-sectional area, but shifted soleus muscle toward a slower phenotype, as shown by an increased number of oxidative type 1 fibers, and increased gene expression of cytochrome c oxidase subunit IV and citrate synthase. The cytokine increased soleus and EDL capillary-to-fiber ratio. PTN overexpression did not prevent soleus muscle atrophy, slow-to-fast transition, and capillary regression induced by SF and HU. Nevertheless, PTN exerted various effects on sarcolemma ion channel expression/function and resting cytosolic Ca2+ concentration in soleus and EDL muscles, in normal loading and after HU. In conclusion, the results show very similar effects of HU and SF on mouse soleus muscle, including activation of specific gene programs. The EDL muscle is able to counterbalance this latter, probably by activating compensatory mechanisms. The numerous effects of PTN on muscle gene expression and functional parameters demonstrate the sensitivity of muscle fibers to the cytokine. Although little benefit was found in HU muscle disuse, PTN may emerge useful in various muscle diseases, because it exerts synergetic actions on muscle fibers and vessels, which could enforce oxidative metabolism and ameliorate muscle performance.

Protective effects of loading combined with astaxanthin on capillary regression of disused muscle

PURPOSEDisuse‐induced muscle atrophy and capillary regression in skeletal muscle are related to overexpression of oxidative stress caused mitochondrial dysfunction. The purpose of the present study was to identify the effect of loading combined with astaxanthin on capillary regression of the soleus muscle induced by hindlimb unloading.METHODSThirty‐five adult male rats were divided into control, hindlimb unloading (HU), HU+astaxanthin (Ax), HU+loading (Lo) and HU+Ax+Lo groups.RESULTSHU resulted in a decreased muscle mass and capillary regression. The loading attenuated the muscle atrophy, which increased the ROS and SOD‐1, resulting in a capillary regression. The combination of loading and astaxanthin attenuated the overexpression of oxidative stress. In addition, the combination increased the expression of e‐NOS, PGC‐1α and succinate dehydrogenase activity, reflecting a protective effect of mitochondrial function and the architecture of capillary network.CONCLUSIONLoading combined with astaxanthin is effective in preventing capillary regression in the soleus muscle induced by hindlimb unloading. Supported by Grants‐in‐Aid for Science Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Treadmill running improves diabetes‐induced capillary regression in skeletal muscle through activation of VEGF and angiopoietin pathways without inhibition of thrombospondin‐1

PURPOSEExercise has been shown to be an effective treatment in the prevention of some complications due to type 2 diabetes (T2DM). The purpose of this study was to investigate the effects of treadmill running on the capillary regression and associated angiogenic factors in the soleus muscle of T2DM rats.METHODSGoto‐Kakizaki (GK) and Wistar rats were randomly divided into an exercise training (T2DM+Ex, Con+Ex) and a sedentary group (T2DM, Con). The T2DM+Ex and Con+Ex rats were run at a low‐intensity on a treadmill 6 times a week for 3 weeks. The capillary in soleus muscle was visualized using 3‐D method. The expression of pro‐angiogenic factors, and anti‐angiogenic factor, thrombospondin‐1 (TSP‐1), in the soleus muscle were determined by TaqMan probe‐based PCR.RESULTSAlthough the capillary volume of the soleus muscle was lower in T2DM than in Con rats, that in T2DM+Ex and Con+Ex was higher than that in Con. VEGF and Angiopoietin pathways in the T2DM+Ex were significantly increased compared with those in other groups although TSP‐1 level increased.CONCLUSIONThese findings suggest that treadmill running improves the regression of capillary in diabetic muscle, and the pro‐angiogenic pathways in diabetic muscle could be up‐regulated by exercise. Supported by Grants‐in‐Aid for Science Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Combined Endothelial and Skeletal Myofiber VEGF Gene Deletion Leads to Capillary Regression in Adult Mouse Hind Limb Muscle

In adult mice, the importance of vascular endothelial growth factor (VEGF) for maintaining skeletal muscle capillaries is unclear. We hypothesized that deletion of the VEGF gene, targeted simultaneously to both endothelial cells and myofibers, would lead to a loss of capillaries in locomotor muscles.MethodsCapillary to fiber ratio (C:F), fiber‐cross sectional area (FCSA), and fiber‐type composition were measured in soleus, plantaris and gastrocnemius cryo‐sections from wild type (WT) and HSA‐Cre‐ERT2 X VEGFLoxP x PDGFb‐iCre‐ERT2 (EC+MyoVEGF−/−) mice. C:F was decreased in soleus from EC+MyoVEGF−/− mice compared to WT (WT, 1.64 ± 0.19, EC+MyoVEGF−/− 1.20 ± 0.19, n=3–9, p &lt; 0.05). FCSA increased in both EC+MyoVEGF−/− soleus and plantaris (soleus: WT, 1953 ± 347 μm2, EC+MyoVEGF−/−, 3148 ± 543 μm2, plantaris: WT, 1731 ± 189 μm2, EC+MyoVEGF−/−, 3261 ± 803 μm2, n=3–9, p &lt; 0.05). EC+MyoVEGF−/− mice also revealed a shift from type IIB to type IIA fibers in the plantaris (type IIB: WT, 66 ± 7 %, EC+MyoVEGF−/−, 48 ± 8 %, type IIA: WT, 19 ± 4%, EC+MyoVEGF−/−, 36 ± 16%, n=3–9, p &lt; 0.05). Unlike previously reported studies in adult skeletal myofiber VEGF‐deficient mice, capillary regression does occur in adult skeletal muscle when VEGF expression is inhibited in both endothelial cells and myofibers.

Differential Effects of Astaxanthin on Oxidative Key Enzyme and Capillarization in the Deep and Superficial Layers of Unloading-induced Atrophied Muscle

[Purpose] The fiber type composition of the muscle hypothetically causes differences in the effects of astaxanthin on capillary regression in the superficial and deep layers of atrophied muscle. The effect of astaxanthin on capillary regression was studied in the superficial and deep layers of the plantaris muscle. [Subjects and Methods] Twenty-four Wistar rats were divided into 4 groups: control, control treated with astaxanthin, hind limb unloading, and hind limb unloading treated with astaxanthin groups. The cross-sectional area and succinate dehydrogenase activity of the plantaris muscle fibers, capillary-to-muscle fiber ratio, and number of capillaries around the muscle fiber were measured using histological images. [Results] In the deep layer, succinate dehydrogenase was activated, and the number of capillaries was decreased in atrophied plantaris muscle. However, these changes were not found in the superficial layer. [Conclusion] Capillary regression in atrophied skeletal muscle was initiated in the deep layer, where muscle fiber characterized by high mitochondrial oxidative enzyme activity is predominantly located, and astaxanthin administration effectively prevent capillary regression.

Tyrosine Kinase Inhibitors Induced Thyroid Dysfunction: A Review of Its Incidence, Pathophysiology, Clinical Relevance, and Treatment

Tyrosine kinase inhibitors (TKI) belong to a new class of molecular multitargeted anticancer therapy which targets different growth factor receptors and hence attenuates cancer cell survival and growth. Since their introduction as adjunct treatment for renal cell carcinoma and gastrointestinal stromal tumors (GIST), a number of reports have demonstrated that TKI can induce thyroid dysfunction which was especially more common with sunitinib maleate. Many mechanisms with respect to this adverse effect of tyrosine kinase inhibitors have been proposed including their induction of thyroiditis, capillary regression in the thyroid gland, antithyroid peroxidase antibody production, and their ability to decrease iodine uptake by the thyroid gland. Of interest is the observation that TKI-induced thyroid dysfunction may actually be protective as it was shown to improve overall survival, and it was suggested that it may have a prognostic value. Followup on thyroid function tests while patients are maintained on tyrosine kinase inhibitor is strongly recommended. When thyroid dysfunction occurs, appropriate treatment should be individualized depending on patients symptoms and thyroid stimulating hormone level.

Protective effects of astaxanthin supplementation on capillary regression of disuse atrophied muscle.

<b>Protective effects of astaxanthin supplementation on capillary regression of disuse atrophied muscle. </b>

Protective effects of astaxanthin on capillary regression in atrophied soleus muscle of rats

The capillary regression in skeletal muscles associated with a chronic decrease in activity is related to a dysfunction of endocapillary cells induced by over-expression of oxidative stress. We hypothesized that treatment with astaxanthin, an antioxidant, would attenuate the oxidative stress induced by decreased skeletal muscle use, and that this attenuation would prevent the associated capillary regression. The purpose of the present study was to investigate the antioxidant and preventive effects of astaxanthin on capillary regression in the soleus muscle during hindlimb unloading. Twenty-four adult male Wistar rats were assigned randomly either to a control, control plus astaxanthin treatment, hindlimb unloaded or hindlimb unloaded plus astaxanthin treatment group for 7 days. Hindlimb unloading resulted in a decrease in mean soleus absolute weight, capillary number, volume and luminal diameter. The accumulation of reactive oxygen species and the over-expression of superoxide dismutase (SOD-1), a decrease in the levels of vascular endothelial growth factor (VEGF) and its receptors, an inhibition of the angiopoietin pathway and an increase of thrombospondin-1 (TSP-1), as an anti-angiogenic factor were showed. Administration of astaxanthin attenuated the changes in SOD-1 and VEGF, up-regulated the angiogenic factors and reduced the capillary regression in the soleus of hindlimb unloaded rats. In addition, the VEGF-to-TSP1 ratio was higher in the astaxanthin treated groups than in the control and HU groups. These results suggest that astaxanthin may be an effective treatment to counter the detrimental effects of a chronic decrease in skeletal muscle use on the capillary network and associated angiogenic pathways.

Pressure Overload Induces Early Morphological Changes in the Heart

Cardiac hypertrophy, whether pathological or physiological, induces a variety of additional morphological and physiological changes in the heart, including altered contractility and hemodynamics. Events exacerbating these changes are documented during later stages of hypertrophy (usually termed pathological hypertrophy). Few studies document the morphological and physiological changes during early physiological hypertrophy. We define acute cardiac remodeling events in response to transverse aortic constriction (TAC), including temporal changes in hypertrophy, collagen deposition, capillary density, and the cell populations responsible for these changes. Cardiac hypertrophy induced by TAC in mice was detected 2 days after surgery (as measured by heart weight, myocyte width, and wall thickness) and peaked by day 7. Picrosirius staining revealed increased collagen deposition 7 days after TAC; immunostaining and flow cytometry indicated a concurrent increase in fibroblasts. The findings correlated with angiogenesis in TAC hearts; a decrease in capillary density was observed at day 2, with recovery to sham-surgery levels by day 7. Increased pericyte levels, which were observed 2 days after TAC, may mediate this angiogenic transition. Gene expression suggests a coordinated response in growth, extracellular matrix, and angiogenic factors to mediate the observed morphological changes. Our data demonstrate that morphological changes in response to cardiovascular injury occur rapidly, and the present findings allow correlation of specific events that facilitate these changes.

Murine double minute‐2 expression is required for capillary maintenance and exercise‐induced angiogenesis in skeletal muscle

Exercise-induced angiogenesis is a key determinant of skeletal muscle function. Here, we investigated whether the E3 ubiquitin ligase murine double minute-2 (Mdm2) exerts a proangiogenic function in exercised skeletal muscle. Mdm2 hypomorphic (Mdm2(Puro/Δ7-9)) mice have a 60% reduction in Mdm2 expression compared with that in wild-type animals. Capillary staining on muscle sections from Mdm2(Puro/Δ7-9) sedentary mice with a wild-type or knockout background for p53 revealed that deficiency in Mdm2 resulted in 20% capillary regression independently of p53 status. In response to one bout of exercise, protein expression of the proangiogenic vascular endothelial growth factor-A (VEGF-A) was increased by 64% in muscle from wild-type animals, and endothelial cell outgrowth from exercised muscle biopsy samples cultured in a 3-dimensional collagen gel was enhanced by 37%. These proangiogenic responses to exercise were impaired in exercised Mdm2(Puro/Δ7-9) mice. Prolonged exercise training resulted in increased Mdm2 protein expression (+49%) and capillarization (+24%) in wild-type muscles. However, exercise training-induced angiogenesis was abolished in Mdm2(Puro/Δ7-9) mice. Finally, exercise training restored Mdm2, VEGF-A, and capillarization levels in skeletal muscles from obese Zucker diabetic fatty rats compared with those in healthy animals. Our results define Mdm2 as a crucial regulator of capillary maintenance and exercise-induced angiogenesis in skeletal muscle.