Capillary Remodeling Research Articles

Abstract 4116949: Specialized Pericyte Subtypes in the Pulmonary Capillary

Introduction: Lung pericytes (PCs) are mural cells in close contact with endothelial cells (ECs) in the microvasculature. A significant challenge in investigating PC biology is largely due to the absence of a unique cell marker, making it difficult to distinguish them from other mural cell populations. The identification of such a marker would allow investigators to describe the role of PCs in various diseases including pulmonary arterial hypertension. Hypothesis: We hypothesize that HIG1 hypoxia-inducible domain family member 1B ( Higd1b ) is exclusively expressed in lung PCs, which contributes to hypoxia (Hx)-induced vascular remodeling. Methods: We utilized single-cell RNA sequence (scRNA-seq) databases, spatial transcriptomics, and RNAscope from human and murine lungs to identify a PC-specific cell marker and compare the gene expression between PC subtypes. We utilized Cre-LoxP and CRISPR technology to construct a novel tamoxifen-inducible Higd1b-CreERT2 knock-in mouse model and performed lineage-tracing studies to describe the role of PC subtypes in Hx-induced pulmonary hypertension (PH). Results: ScRNA-seq analysis from the lungs of humans and mice identified Higd1b as a specific gene marker for PCs whose expression is absent in other mural cell populations. Validation with a reporter mouse line Higd1b-CreERT2::R26-tdT confirmed Higd1b-Cre+ cells specifically label PCs and no other mural cells ( Fig 1A ). Lineage tracing in the Hx-induced murine model of PH demonstrated the accumulation of PCs in the muscularized distal arterioles ( Fig 1B ). Through scRNA-seq and immunofluorescence validation, we identified two HIGD1B + PC subtypes that exist in the pulmonary capillary: Type 1 PCs, which are quiescent in the capillaries, and Type 2 PCs exhibit multipotent cell-like properties and accumulate in the arterioles after exposure to Hx. Furthermore, we found Type 2 PCs transited into SMC-like cells via the upregulation of Vimentin, contributing to vascular remodeling in Hx-induced PH. Conclusion: We identified Higd1b as a unique marker for PCs and generated a novel Higd1b-CreERT2 mouse that specifically labels PCs in the lungs. The discovery of PC-subtype specialization advances our understanding of lung pericyte biology and PC’s contribution to capillary remodeling under pathological conditions.

Effect of pomegranate peel with/without autologous bone marrow on healing of acute cutaneous wounds in alloxan-induced diabetic rabbits.

Healing of bum wounds is commonly associated with many complications. Every year various new repair materials are developed and experimentally used for treating burn wounds. Humans with diabetes mellitus usually suffer from chronic wound healing. Vascular, neuropathic, immune function, and biochemical abnormalities each contribute to the altered tissue repair. One underlying factor that accompanies all diabetic ulcerations is poor vascular flow, a circumstance that impedes proper wound healing. Numerous studies have highlighted the importance of adequate vascular sufficiency and vessel proliferation in tissue repair and the lack thereof in diabetic wound healing. Other studies have looked at whether disarrayed capillary remodeling and maturation of vessels might play a role in impaired diabetic wound healing. This investigation has been planned to report the influence of treatment with a mixture of both the powder of pomegranate peel (PP) accompanied with an autologous bone marrow (BM) on the cure of burn injuries in experimentally induced diabetic rabbits. Alloxan monohydrate has been applied to create diabetes in 50 rabbits. Then in each rabbit, two deep second-degree burn wounds were experimentally created. The animals were then divided randomly into 5 treatment sections: non-treatment controls (C1), treated with an available commercial powder for wound (C2), treatment with powder of PP, treatment with alone BM, and the final group treated with PP powder with bone marrow (PPBM). The speed of wound closure and the histopathological changes during healing were measured. The levels of the biomarkers of rabbit platelet-derived growth factor AA (PDGF-AA) and rabbit protease-activated receptor 1 (PAR-1) were measured on days 0, 4, 8, and 12. Wound healing was markedly more rapid in all the treatment groups versus the control non-treated group. Interestingly, a rapid wound cure was significantly observed in the PPBM group versus the other treatment ones. The histological assessment clarified a significant elevation in the fibroblast and collagen scores in the PPBM group versus the other sections. In addition, there were significant increases in the serum levels of the biomarkers PDGF-AA and PAR-1 among groups. Dependent on the results of current research, it can be concluded that both PP powder with BM PPBM significantly accelerate the healing process of burn wounds in experimentally induced diabetic rabbits.

Cardiovascular Insights for the Appropriate Management of Chronic Venous Disease: A Narrative Review of Implications for the Use of Venoactive Drugs.

Evidence suggests that chronic venous disease (CVD) may be a cardiovascular disorder, as patients with CVD are prone to developing arterial (atherosclerosis) and venous (thromboembolism) diseases. This may be partly explained by shared risk factors. Thus, patients with CVD or cardiovascular disease require careful history-taking and physical assessment to identify coexisting pathologies and risk factors. This article summarises a symposium at the XIX World Congress of the International Union of Phlebology held in Istanbul, Turkey, in September 2022. Common pathophysiological features of CVD and cardiovascular disease are endothelial injury, hypercoagulability and systemic inflammation. In CVD, inflammation primarily affects the microcirculation, with changes in capillary permeability, vein wall and valve remodelling and increase in oxidative stress. Once patients develop symptoms/signs of CVD, they tend to reduce their physical activity, which may contribute to increased risk of cardiovascular disease. Data show that the presence of CVD is associated with an increased risk of cardiovascular disease, including peripheral arterial disease and heart failure (HF), and the risk of adverse cardiovascular events increases with CVD severity. In addition, patients with cardiovascular disease, particularly those with HF, are at increased risk of venous thromboembolism (VTE) and should be assessed for VTE risk if they are hospitalised with cardiovascular disease. Therefore, CVD management must include a multi-specialty approach to assess risk factors associated with both the venous and arterial systems. Ideally, treatment should focus on the resolution of endothelial inflammation to control both CVD and cardiovascular disease. International guidelines recommend various conservative treatments, including venoactive drugs (VADs), to improve the symptoms/signs of CVD. Micronized purified flavonoid fraction (MPFF) is a VAD, with high-quality evidence supporting its use in relieving symptoms/signs of CVD and improving quality of life. Moreover, in large-scale observational studies, MPFF has shown superior effectiveness in real-world populations compared with other VADs. Video Abstract. (MP4 97173 kb).

Cardioprotective Effect of Soy Protein on a High-Salt Diet in Cynomolgus Monkeys

Excessive salt intake is accompanied by the development of cardiovascular disorders, not always associated with an increase in blood pressure (BP). Given the cardioprotective effect of soy proteins in chronic kidney disease, the question arose of the possibility of leveling dietary interventions, in particular soy proteins, the damaging effect of a high-salt diet on the cardiovascular system. The aim of this work is to study the effect of long-term use of a diet high in NaCl and soy protein on myocardial remodeling and skin histomorphology in monkeys. The study was performed on male Javan macaques (Macaca fascicularis). The control group received a standard diet (2 g NaCl/kg feed). The second was a high-salt diet (8 g NaCl/kg feed), the third was a high-salt diet and SUPRO760 soy protein (200 g/kg feed). Echocardiography, registration of BP and heart rate were performed at baseline, after 4 and 12 months. After 12 months, a histological examination of the musculocutaneous flap was performed. In all animals, BP and heart rate did not change significantly during 12 months. In macaques on a high-salt diet, by the end of the study, deterioration in systolic and diastolic functions of the left ventricle (LV) was noted. In animals receiving additional soy protein, these changes leveled out. After 12 months, macaques fed soy protein had LV myocardial mass smaller and higher LV contractility than animals fed excess salt without soy protein. In monkeys on a high-salt diet, accumulation of collagen fibers in the hypodermis, hyalinization of the cytoplasm of capillary smooth muscle cells, perivascular and perineural edema of the reticular dermis were revealed. In animals treated with soy protein, skin capillary remodeling was less pronounced. Thus, high salt intake leads to adverse structural and functional disorders of the heart and blood vessels in cynomolgus monkeys, not associated with an increase in blood pressure. The inclusion of soy isolate in the diet reduces the negative effects of a high-salt diet on the cardiovascular system.

Microcirculation and Physical Exercise In Hypertension.

Hypertension is associated with important alterations in the morphology of small arteries and arterioles. Vascular-specific manifestations are changes in the structure and function of vascular smooth muscle cells, extracellular matrix, perivascular tissues, and endothelial cells. Arteriole and capillary remodeling and capillary rarefaction have been observed in hypertensive animals and human beings which contribute to increased vascular resistance. An impairment of different angiogenetic factors, such as VEGF (vascular endothelial growth factor), VEGFR-2 (vascular endothelial growth factor receptor-2), TIMP-1 (tissue inhibitor matrix metalloproteinases-1), and TSP-1 (thrombospondin-1), seems to be responsible for the reduction of the microvascular network. Exercise training has been shown to improve vascular structure and function in hypertension not only in the large arteries but also in the peripheral circulation. Exercise training may regress microvascular remodeling and normalize capillary density, leading to capillary growth possibly by increasing proangiogenic stimuli such as VEGF. Exercise enhances endothelium-dependent vascular relaxation through nitric oxide release increase and oxidative stress reduction. Other mechanisms include improved balance between prostacyclin and thromboxane levels, lower circulating levels of endothelin-1, attenuation of infiltration of immune cells into perivascular adipose tissue, and increase of local adiponectin secretion. In addition, exercise training favorably modulates the expression of several microRNAs leading to a positive modification in muscle fiber composition. Identifying the bioactive molecules and biological mechanisms that mediate exercise benefits through pathways that differ from those used by antihypertensive drugs may help to improve our knowledge of hypertension pathophysiology and facilitate the development of new therapeutic strategies.

MICROCIRCULATORY ALTERATIONS IN STABLE CORONARY ARTERY DISEASE PATIENTS WITH CONCOMITANT COVID-19.

The aim: To evaluate the alterations in microcirculation of stable coronary artery disease (SCAD) patients with concomitant COVID-19. Materials and methods: The cross-sectional study analyzed the data from 80 patients, being subdivided as follows: group 1 (G1) - SCAD without COVID-19 (n=30); group 2 (G2) - SCAD with concomitant COVID-19 (n=25); group 3 (G3) - COVID-19 without SCAD (n=25). The control group included 30 relatively healthy volunteers. The state of microcirculation was assessed by nailfold videocapillaroscopy (NVC) and laser Doppler flowmetry (LDF). Results: NVC data from G2 revealed the sings of capillary bed remodeling, along with the most pronounced decrease in capillary (arteriolar part of the loop) blood flow velocity (vs. G1 and G3). LDF data from G2 were evident for the alterations in both endothelium-dependent and -independent mechanisms of microvascular flow regulation. The 72 % of G2 constituted the cases of microcirculatory hemodynamic «congestion-stasis» (MHCS) type (characterized by the decreased laser Doppler perfusion index and reduced endothelium-dependent microvascular reactivity [MVR]), and the cases of mixed type with reduced MVR. The pooled hyporeactive profile (of both MHCS type and a mixed type with reduced MVR) demonstrated the higher frequency of G2 patients (40 %), as against 11 % in the pooled alternative hemodynamic group (p<0,001) (included 80 % of cases with preserved MVR). Conclusions: G2 profile demonstrated the predomination of patients, possessing a MHCS type or a mixed type with reduced MVR. The pooled microcirculatory hyporeactive profile was presented with G2 cases to a greater extent, than in the pooled profile with predominantly preserved MVR.

Microvascular remodeling following skin injury.

The aim of this study was to describe possible remodeling (i.e., dilatation and elongation) of papillary capillaries induced by increased oxygen demand for the repair process following a skin wound. Computer-assisted video microscopy was used to examine 10healthy volunteers before (baseline) and after (≈1h and ≈24h) an incision (5mm long and 1mm deep) on the forearm, 0-1mm and 30mm (control site) from the incision. We defined categories from 0 (low) to 3 (high) to grade dilatation and elongation of the nutritive papillary capillaries, as well as the visibility of the superficial vascular plexus. Approximately 10000 capillaries from 200 films were scored. The nutritive papillary capillaries were dilated and elongated (p<0.01) after ≈24h; that is, elongation (score 1.9±0.9) vs baseline (score 0.9±0.6), p<0.01 and dilatation (score 2.2±0.7) vs baseline (score 0.3±0.3), p<0.01. Superficial plexus visibility increased (p<0.01) after ≈1h (score 2.0±0.7) and ≈24h (score 2.7±0.3) vs baseline (score 0.8±0.4). The superficial vascular skin plexus showed enhanced visibility already ≈1h after the skin trauma. Morphological remodeling in the nutritive papillary capillaries-dilatation and elongation after ≈24h-facilitate increased O2 supply.

Identification of venular capillary remodelling: a possible link to the development of periodontitis?

PurposeThe present study measured changes in arteriolar and venular capillary flow and structure in the gingival tissues during the development of plaque-induced gingival inflammation by combining dynamic optical coherence tomography (OCT), laser perfusion, and capillaroscopic video imaging.MethodsGingival inflammation was induced in 21 healthy volunteers over a 3-week period. Gingival blood flow and capillary morphology were measured by dynamic OCT, laser perfusion imaging, and capillaroscopy, including a baseline assessment of capillary glycocalyx thickness. Venular capillary flow was estimated by analysis of the perfusion images and mean blood velocity/acceleration in the capillaroscopic images. Readings were recorded at baseline and weekly over the 3 weeks of plaque accumulation and 2 weeks after brushing was resumed.ResultsPerfusion imaging demonstrated a significant reduction of gingival blood flow after 1 and 2 weeks of plaque accumulation (P<0.05), but by 3 weeks of plaque accumulation there was a more mixed picture, with reduced flow in some participants and increased flow in others. Participants with reduced flux at 3 weeks also demonstrated venular-type flow as determined by perfusion images and evidence of the development of venular capillaries as assessed by the velocity/acceleration ratio in capillaroscopic images. After brushing resumed, these venular capillaries were broken down and replaced by arteriolar capillaries.ConclusionsAfter 3 weeks of plaque accumulation, there was wide variation in microvascular reactions between the participants. Reduced capillary flow was associated with the development of venular capillaries in some individuals. This is noteworthy, as an early increase in venous capillaries is a key vascular feature of cardiovascular disease, psoriasis, Sjögren syndrome, and rheumatoid arthritis—diseases with a significant association with the development of severe gingival inflammation, which leads to periodontitis. Future investigations of microvascular changes in gingival inflammation might benefit from accurate capillary flow velocity measurements to assess the development of venular capillaries.

Abstract 11240: Capillary Rarefaction and Right Ventricular Dysfunction in Advanced HFrEF: Human Tissue Histomorphometry Analysis

Introduction: Right ventricular dysfunction (RVD) limits survival in heart failure (HF). Besides pulmonary hypertension (PH), load-independent mechanisms may contribute to RVD. In experimental PH, loss of myocardial capillary density (rarefaction) was implicated in the faster decline of RV function. Hypothesis: To elucidate the role of rarefaction in development of RVD in HFrEF. Methods: We examined RV fractional area change (RV FAC%) prior heart Tx (median -57 days) in 124 consecutive HTx candidates (non-LVAD) and harvested RV free wall at HTx from patients in the bottom (Q1: 10-17%) and top (Q4: 32-42%) quartiles of pre-HTx RV FAC%. As controls (Con), we obtained RV samples from 20 unused heart donors. Quantitative histomorphometry and mRNA gene expression were studied. Results: HF (65% non-ischemic) and Con were matched by similar age, gender and BMI. HF patients had larger and more dysfunctional RV (RVD1 46 vs 32 mm, p&lt;0.001, RV FAC 25±10%). Compared to Con, RV from HF displayed significant upregulation of genes for PDK4 (Pyruvate Dehydrogenase Kinase4), NPPA (Natriuretic peptide A), BDH1 (β-OH-butyrate dehydrogenase), and downregulation of MYH6 (Myosin Heavy Chain 6). In HF vs Con, RV CM diameter was increased (25±6 vs 15±4 μm, p&lt;0.001), but RV capillary density was lower (939±474 vs 1457±670 n/mm -2 , p=0.007), even if adjusted to CM diameter (39 vs 102 mm -1 , p=0.0005) or area (Fig). HF patients from Q1 and Q4 RV FAC differed by higher PH (mPA 37 vs 31 mmHg, p=0.01), larger RV size (48 vs 43 mm, p=0.01) and higher PCWP (27 vs 22, p=0.002), but there was no difference in capillary density (unadjusted or per CM diameter/area, Fig) or gene expression profile, HF etiology or comorbidities. Conclusions: Compared to Con, RV of HF patients shows reduced capillary density, metabolic and myofilament remodeling. Yet, HF patients with lower RV FAC% do not differ from those with less impaired RV function, suggesting that capillary rarefaction per se does not explain progression of RVD in HF.

Quantification of vascular and neuronal changes in the peripapillary retinal area secondary to diabetic retinopathy

PurposeTo investigate and quantify peripapillary vascular and neuronal changes secondary to diabetic retinopathy, using spectral-domain optical coherence tomography (OCT) and OCT angiography (OCTA).DesignThis was a cross-sectional study.Methods51 eyes of 51...

The vascularization, innervation and myogenesis of early regenerated tail in Gekko japonicus.

Many species of lizards are capable of tail regeneration. There has been increased interest in the study of lizard tail regeneration in recent years as it is an amenable regeneration model for amniotes. In this study, Gekko japonicus was used as a model to investigate the initiation of vascularization, innervation and myogenesis during tail regeneration. We found that angiogenesis and axon regeneration occurred almost simultaneously within 4days post amputation. The results showed that the endothelial cells of the original vasculature proliferated and extended into the blastema as capillary vessels, which inter-connected to form a capillary network. The nerve fibers innervated the regenerated tissue from the original spinal cord and dorsal root ganglia, and the fiber bundles increased during 14days. Regenerating muscle tissues emerged 2weeks after amputation. PAX3 and PAX7 expression were detected during myogenesis, with PAX7 showing a continuous increase in expression from day 3 until the day 14, whereas PAX3 reached a peak level on day 10day post amputation, and then declined quickly to level as normal control on day 14. PCNA and PAX3 double-positive satellite cells were observed in the original rostral tissues, indicating the involvement of satellite cell proliferation during tail regeneration. Taken together, these data suggest that tail regeneration in Gekko japonicus involved rapid angiogenesis from the beginning to the day 10 and followed by capillary remodeling. The innervation of regenerated tail was significant on day 4 and increased gradually during regeneration, while the regenerated muscle tissues was obvious on day 14 after amputation.

Влияние модели разового вахтового труда в высокогорье на поведение и структурную организацию мозжечка

In Kyrgyzstan, 94% of the entire territory of the country is occupied by mountains. There are significant resources located here, the development of which is often associated with the temporary ascent to significant heights and descent to the low mountains of specialists in various fields of work. At the same time, information about the state of brain structures and the behavior of animals and humans in these conditions is scarce. Objective: to study the influence of the model of a one-time 8-hour shift work in the highlands on the histophysiology of the cerebellum and individual behavior of rats. The work was performed on 28 white mongrel male rats weighing 250–310 g. The low-mountain series of the experiment was carried out at an altitude of 760 m above sea level (Bishkek). The high-altitude series was modeled on the Tuya-Ashu pass-3200 m above sea level (Kyrgyzstan). Behavioral activity was evaluated using the Open field method, muscle strength according to the S. V. Speransky method on the 3rd day of the experiment. The microcirculation of the cerebellum was studied microscopically under the Olympus B×40 light microscope (Japan). Statistical processing of the obtained data was carried out in the SPSS 16.0 program. In the highlands, the indicators of the mink reflex increase by 1.43 times, and the level of defecation increases by 8.5 times, which is a marker of increased vegetative activity of the body. Remodeling of cerebellar angioarchitectonics in the highlands is characterized by hypercapillarization, signs of blood stagnation, perivascular edema, enlargement of nucleoli, moderate hyperchromia of neurons of the molecular and granular layers. Thus, in the highlands, changes in behavioral activity are more pronounced than the remodeling of capillaries, neurons and glial elements, which are adaptive in nature.

Influences of high fat diet and ischemia on skeletal muscle pericytes

Pericytes are mural cells on the abluminal surface of capillaries that play an essential role in capillary stabilization. They also regulate angiogenesis by guiding vessel sprouting and the maturation of newly formed sprouts. Furthermore, pericytes may have adipogenic differentiation potential. Muscle ischemia, as seen in peripheral artery disease, causes oxidative and nutrient-deprivation stress and ultimately death of skeletal myocytes. Ischemia is a stimulus for angiogenesis, a crucial process for muscle regeneration. However, newly formed capillaries are structurally and functionally aberrant, which might be explained by dysfunction of pericytes. Recently, we showed that high-fat (HF) diet in mice provokes a shift in skeletal muscle pericytes towards a pre-adipocyte phenotype. This alteration may disrupt capillary remodeling processes and contribute to the worsened prognosis of PAD patients with diabetes. Thus, the purpose of this study was to assess the effects of HF diet and ischemia on skeletal muscle pericytes. We hypothesized that the number of capillary-associated pericytes will be altered by each HF diet and ischemia and together, they may exert an additive effect. Two groups of 8 weeks old NG2/DsRed mice (that express DsRed protein under the control of the pericyte NG2 promoter) were fed normal (NC) or high fat (HF) diets (10% or 60% kcal from fat, respectively) for two weeks. The second group also underwent unilateral femoral artery ligation surgery to induce ischemia and were euthanized 14 days post-ischemia. Analysis of EDL muscle longitudinal sections showed that HF diet decreased pericyte number/100 μm2 vascular area (30.1 ± 0.6 (n=5) vs. 23.1 ± 2.4 (n=6) in NC and HF, respectively p<0.05). PDGFRβ+ pericytes isolated from the muscles of these mice exhibited a HF diet-induced increase in the relative mRNA levels of leptin (0.51 ± 0.11 (n=7) vs. 0.83 ± 0.16 (n=6) in NC and HF, respectively p<0.05) and the pre-adipocyte commitment marker Zfp423 (0.92 ± 0.11 (n=7) vs. 1.10 ± 0.14 (n=7) in NC and HF, respectively p<0.05), suggesting a shift in pericyte phenotype. Ischemic muscles of both NC and HF-fed mice had increased numbers of capillary-associated pericytes compared to non-ischemic muscle (1.6 ± 0.4 and 1.4 ± 0.1fold increases in NC and HF, respectively. n=3, p<0.05). Capillary area relative to muscle area did not differ with diet or ischemia. These samples will be used to quantify pericyte proliferation and markers of pericyte phenotype in the ischemic muscles. These data provide a valuable first step in defining the behavior and functions of pericytes during muscle adaptations to the pathophysiological conditions of HF diet and ischemia.

Longitudinal Changes on Optical Coherence Tomography Angiography in Retinal Vein Occlusion.

Background: To evaluate the longitudinal changes on optical coherence tomography angiography (OCTA) in retinal vein occlusion (RVO). Methods: Retrospective study of patients with RVO treated with intravitreal anti-vascular endothelial growth factors (VEGF) for macular edema. Foveal avascular zone (FAZ) area, vessel density (VD), vessel length density (VLD), and adjusted flow index (AFI) were calculated. The unaffected eye of each participant was used as a control. Results: Twelve RVO eyes were included, receiving 6 ± 3 anti-VEGF injections over a follow-up of 10.4 ± 3.1 months. Compared to fellow eyes, RVO eyes had lower VD and VLD at inclusion (p = 0.07 and p = 0.04) and last visit (p = 0.002 and p < 0.001). VD, AFI, and VLD did not change over time, while FAZ area increased in RVO eyes (+0.016 ± 0.024 mm2, p = 0.04). AFI correlated with duration of disease (r = 0.63, p = 0.02). Visual acuity was inversely related to VD and VLD over the follow-up. Conclusions: OCTA parameters remained stable with sustained anti-VEGF treatment in RVO, while changes in the FAZ area may suggest capillary remodeling after RVO.

Afferent Lymphatic Transport and Peripheral Tissue Immunity.

Lymphatic vessels provide an anatomical framework for immune surveillance and adaptive immune responses. Although appreciated as the route for Ag and dendritic cell transport, peripheral lymphatic vessels are often not considered active players in immune surveillance. Lymphatic vessels, however, integrate contextual cues that directly regulate transport, including changes in intrinsic pumping and capillary remodeling, and express a dynamic repertoire of inflammatory chemokines and adhesion molecules that facilitates leukocyte egress out of inflamed tissue. These mechanisms together contribute to the course of peripheral tissue immunity. In this review, we focus on context-dependent mechanisms that regulate fluid and cellular transport out of peripheral nonlymphoid tissues to provide a framework for understanding the effects of afferent lymphatic transport on immune surveillance, peripheral tissue inflammation, and adaptive immunity.

Remodeling of the Microvasculature: May the Blood Flow Be With You.

The vasculature ensures optimal delivery of nutrients and oxygen throughout the body, and to achieve this function it must continually adapt to varying tissue demands. Newly formed vascular plexuses during development are immature and require dynamic remodeling to generate well-patterned functional networks. This is achieved by remodeling of the capillaries preserving those which are functional and eliminating other ones. A balanced and dynamically regulated capillary remodeling will therefore ensure optimal distribution of blood and nutrients to the tissues. This is particularly important in pathological contexts in which deficient or excessive vascular remodeling may worsen tissue perfusion and hamper tissue repair. Blood flow is a major determinant of microvascular reshaping since capillaries are pruned when relatively less perfused and they split when exposed to high flow in order to shape the microvascular network for optimal tissue perfusion and oxygenation. The molecular machinery underlying blood flow sensing by endothelial cells is being deciphered, but much less is known about how this translates into endothelial cell responses as alignment, polarization and directed migration to drive capillary remodeling, particularly in vivo. Part of this knowledge is theoretical from computational models since blood flow hemodynamics are not easily recapitulated by in vitro or ex vivo approaches. Moreover, these events are difficult to visualize in vivo due to their infrequency and briefness. Studies had been limited to postnatal mouse retina and vascular beds in zebrafish but new tools as advanced microscopy and image analysis are strengthening our understanding of capillary remodeling. In this review we introduce the concept of remodeling of the microvasculature and its relevance in physiology and pathology. We summarize the current knowledge on the mechanisms contributing to capillary regression and to capillary splitting highlighting the key role of blood flow to orchestrate these processes. Finally, we comment the potential and possibilities that microfluidics offers to this field. Since capillary remodeling mechanisms are often reactivated in prevalent pathologies as cancer and cardiovascular disease, all this knowledge could be eventually used to improve the functionality of capillary networks in diseased tissues and promote their repair.

Effects of reloading after chronic neuromuscular inactivity on the three-dimensional capillary architecture in rat soleus muscle

The purpose of the study was to investigate the effects of ambulatory reloading following hindlimb unloading on the three-dimensional (3D) capillary architecture of rat soleus muscle. In this study, 15 male Sprague–Dawley rats were used. The rats were randomly assigned to the following 3 groups: a normal weight bearing control group (CON), 14 days of hindlimb unloading group (HU), and 14 days of hindlimb unloading followed by 7 days of ambulatory reloading group (HU-RL). The capillary diameter and volume were measured using confocal laser microscopy, and capillary number was determined by two-dimensional (2D) capillary staining in the soleus muscle of each group. The capillary diameter and volume as well as the capillary number were significantly lower in the HU group than in the CON group and significantly higher in the HU-RL group than in the HU group. These results provided novel information about the effectiveness of reloading following unloading on not only the 2D increase in capillary number but also the 3D capillary remodeling in the diameter and volume within the unloaded soleus muscle.

Fluorescent angiography imaging of intravitreal active bleeding, due to deep venous thrombosis concomitant to Fournier gangrene

To report a breakthrough bleeding in the vitreous cavity due to deep venous thrombosis, in a case of a middle-aged male patient who suffered concomitantly from Fournier's gangrene. Fluorescent angiography imaging displayed the intravitreal hemorrhage as occurring. We performed fundus fluorescein angiography and optical coherence tomography at baseline and follow-up examinations. During fluorescein angiography we identified, right eye fluorescent blockage corresponding to a pre-retinal, a subhyaloid, and an intraretinal hemorrhage in the posterior pole. Capillary non-perfusion, and capillary remodeling of the far temporal peripheral vasculature was detected as well, the left eye was unremarkable. A breakthrough bleeding in the vitreous cavity of the upper temporal vein branch was caught as it was happening. We did not observe leaking at the macula; our findings were confirmed with optical coherence tomography throughout the follow-up period. Active retinal bleeding has been reported only twice in the past, in these cases, it was attributed to superficial venous vessel rupture due to vitreous traction or Valsalva-like retinopathy at the site of neovascularization. Active retinal vein bleeding during a fluorescein angiography, secondary to deep venous thrombosis due to Fournier gangrene, has not been previously reported.

Sex Differences In Quadriceps Angiogenic Signaling And Muscle Capillary Supply After ACL Injury

Following an Anterior Cruciate Ligament (ACL) reconstruction, females have worse functional outcomes; however, skeletal muscle biology has preferentially been studied in males. Muscle adaptation and recovery from injury are intimately tied to the muscle capillary network, which delivers oxygen, nutrients, and hormones to muscle fibers. PURPOSE: To examine differences in skeletal muscle angiogenic signaling and capillary supply in males and females after ACL injury. METHODS: Vastus lateralis (VL) biopsies were collected (24.6 ± 5.5 yr; 8M, 5F) from the ACL injured (INJ) and non-injured (NI) leg before reconstruction. Samples were assessed for vascular endothelial growth factor receptor 1 and 2 (VEGFR1 and VEGFR2) by western blot. Capillary to fiber ratio (C:F), capillary to fiber perimeter exchange index (CFPE), and capillary tortuosity (% fiber border directly contacting capillary wall) were assessed by immunohistochemistry. RESULTS: The percentage of phosphorylated relative to total VEGFR2 was not different between INJ and NI, but was lower in females (76.9 ± 4.1%) compared to males (89.2 ± 3.2%; P = 0.043). VEGFR2 abundance tended to be higher (P = 0.098) and C:F was lower (INJ: 2.3 ± 0.2 capillary•fiber-1, NI: 2.6 ± 0.2 capillary•fiber-1; P = 0.018) in INJ compared to NI, but neither parameter was different between sexes. VEGFR1 abundance displayed a sex by injury interaction (P = 0.004), with females having greater abundance of VEGFR1 in INJ (548 ± 54 A.U.) compared to NI (478 ± 53 A.U.; P = 0.050), while males showed the opposite (NI: 461 ± 42 A.U., INJ: 383 ± 42 A.U.). CFPE was lower in INJ compared to NI (INJ: 5.1 ± 0.3 capillary•1000μm-1, NI: 5.8 ± 0.3 capillary•1000μm-1; P = 0.002), and post-hoc analysis revealed that the difference was driven by females. Capillary tortuosity was lower in INJ (13 ± 2%) compared to NI (17 ± 2%) for females only (P = 0.006). CONCLUSION: Differences in angiogenic signaling between males and females in both INJ and NI limbs were evident, and ACL injury resulted in an exacerbated deficit in muscle capillary supply for females. These results support the idea that sex-specific differences in VL capillary network remodeling following ACL injury contribute to different functional outcomes following reconstruction and rehabilitation. Supported by NIH grants: R01 AR072061 and K23 AR062069.

Spermidine supplementation and voluntary activity differentially affect obesity-related structural changes in the mouse lung.

Obesity is associated with lung function impairment and respiratory diseases; however, the underlying pathophysiological mechanisms are still elusive, and therapeutic options are limited. This study examined the effects of prolonged excess fat intake on lung mechanics and microstructure and tested spermidine supplementation and physical activity as intervention strategies. C57BL/6N mice fed control diet (10% fat) or high-fat diet (HFD; 60% fat) were left untreated or were supplemented with 3 mM spermidine, had access to running wheels for voluntary activity, or a combination of both. After 30 wk, lung mechanics was assessed, and left lungs were analyzed by design-based stereology. HFD exerted minor effects on lung mechanics and resulted in higher body weight and elevated lung, air, and septal volumes. The number of alveoli was higher in HFD-fed animals. This was accompanied by an increase in epithelial, but not endothelial, surface area. Moreover, air-blood barrier and endothelium were significantly thicker. Neither treatment affected HFD-related body weights. Spermidine lowered lung volumes as well as endothelial and air-blood barrier thicknesses toward control levels and substantially increased the endothelial surface area under HFD. Activity resulted in decreased volumes of lung, septa, and septal compartments but did not affect vascular changes in HFD-fed mice. The combination treatment showed no additive effect. In conclusion, excess fat consumption induced alveolar capillary remodeling indicative of impaired perfusion and gas diffusion. Spermidine alleviated obesity-related endothelial alterations, indicating a beneficial effect, whereas physical activity reduced lung volumes apparently by other, possibly systemic effects.