Changes In Capillary Density Research Articles

Abstract 55: Mouse Offspring Exposed to Preeclampsia/Eclampsia-like Symptoms Exhibit Changes in Regional Cerebral Perfusion at 2 months of age

Children born to mothers with preeclampsia, a hypertensive pregnancy disorder, or eclampsia, new-onset seizures during pregnancy, are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared to those born from normal pregnancies. The contributing mechanisms are unknown. The objective of this study was to determine whether mice exposed to reduced uteroplacental perfusion (RUPP), to mimic preeclampsia with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in regional cerebral perfusion changes at 2 months of age. On gestational day (GD) 13.5, pregnant C57BL/6 mice underwent sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD 18.5. At 2 months of age, cerebral perfusion was measured using Laser Speckle Imaging, and averaged to obtain mean data per sex, per litter (n = 3-6 average datapoints per group). Perfusion data were normalized to the area of each region of interest. Data were analyzed using Two-Way ANOVA. Our findings indicate a reduction in cerebral perfusion in offspring exposed indirectly to RUPP specifically of the right parietal cortex (p = 0.013), superior sagittal sinus (p = 0.003), cerebellum (p = 0.003) and whole brain (p = 0.021). We also observed an overall significant reduction in perfusion, after indirect PTZ exposure, in the right parietal cortex (p = 0.002), transverse sinus (p = 0.003), and cerebellum (p < 0.001); and increase in prefrontal cortex perfusion (p = 0.001). Further observation showed an overall difference in hematocrit (p = 0.001), SPO2 (p < 0.001), and cerebellum water content (p = 0.007) after indirect PTZ exposure. There was no difference in perfusion of the left parietal cortex, body weight, organ weight (except brain, where RUPP exposure led to overall increased brain weight; p = 0.030). Together, our results are consistent with the hypothesis that exposure to preeclampsia/eclampsia conditions leads to changes in offspring cerebrovascular function, with a net reduction in perfusion. Reduced cerebral perfusion is generally associated with reduced cognitive function. Whether this occurs along with changes in capillary density, or is exacerbated with age are areas of active investigation.

Effects of cardiac rehabilitation on in vivo nailfold microcirculation in patients with cardiovascular disease.

This study aimed to explore the impact of cardiac rehabilitation (CR) on in vivo and ex vivo microcirculation, exercise capacity, and oxidative stress in patients with cardiovascular disease (CVD). The study included patients with acute coronary syndrome (ACS; n = 45; age, 69.0 ± 14.1 years) and heart failure (HF; n = 66; age, 77.3 ± 10.7 years) who underwent supervised CR during hospitalization. The control group comprised patients without CVD (NCVD; n = 20; age, 75.9 ± 11.2 years). In vivo microcirculatory observations using nailfold video capillary endoscopy at rest and during hyperemia, exercise capacity, and oxidative stress were assessed at baseline and 12 weeks after discharge. Baseline capillary densities were significantly lower in the ACS (5.0 ± 1.7 capillaries/mm2) and HF (4.9 ± 1.7 capillaries/mm2) groups than in the NCVD group (6.5 ± 1.1 capillaries/mm2, p < 0.01). Similarly, capillary density during reactive hyperemia was significantly lower in the ACS (5.8 ± 1.7 capillaries/mm2) and HF (5.4 ± 1.8 capillaries/mm2) groups than in the NCVD group (7.3 ± 1.4 capillaries/mm2, p < 0.01). Patients with ACS and HF had increased capillary densities at 12 weeks compared with at baseline (p < 0.05). This improvement was particularly pronounced among post-discharge outpatient CR participants (n = 20). Grip strength, exercise capacity, and oxidative stress improved at 12 weeks. Baseline capillary density changes were positively correlated with grip strength changes (r = 0.45, p < 0.001). CR significantly improved nailfold capillary density in patients with ACS and HF 12 weeks after discharge.

Unraveling the Complex Molecular Interplay and Vascular Adaptive Changes in Hypertension-Induced Kidney Disease.

Angiogenesis, the natural mechanism by which fresh blood vessels develop from preexisting ones, is altered in arterial hypertension (AH), impacting renal function. Studies have shown that hypertension-induced renal damage involves changes in capillary density (CD), indicating alterations in vascularization. We aimed to elucidate the role of the apelin receptor (APLNR), neuronal nitric oxide synthase (nNOS), and vascular endothelial growth factor (VEGF) in hypertension-induced renal damage. We used two groups of spontaneously hypertensive rats aged 6 and 12 months, representing different stages of AH, and compared them to age-matched normotensive controls. The kidney tissue samples were prepared through a well-established protocol. All data analysis was conducted with a dedicated software program. APLNR was localized in tubular epithelial cells and the endothelial cells of the glomeruli, with higher expression in older SHRs. The localization of nNOS and VEGF was similar. The expression of APLNR and nNOS increased with AH progression, while VEGF levels decreased. CD was lower in young SHRs compared to controls and decreased significantly in older SHRs in comparison to age-matched controls. Our statistical analysis revealed significant differences in molecule expression between age groups and varying correlations between the expression of the three molecules and CD.

Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice.

Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. We used mouse models of constitutive endothelial cell-specific Arf6 deletion (Arf6f/- Tie2Cre+) and tamoxifen-inducible Arf6 knockout (Arf6f/f Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere-based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy. Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside-mediated vasodilation. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow-fed mice and glucose intolerance in high-fat diet-fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

Влияние исходных структурных нарушений и послеоперационного изменения перфузии на функциональное восстановление сетчатки после хирургического лечения сквозных макулярных разрывов

Purpose. To evaluate effect of preoperative local structural retinal changes and capillary perfusion in idiopathic full-thickness macular holes (FTMH) on the recovery of functional activity of the retina after surgical treatment. Materials and methods. We used optical coherence tomography (OCT) and OCT-angiography (OCT-A), microperimetry, multifocal electroretinography. In 25 eyes with FTMH the density of capillaries in the superficial and deep capillary plexus (SCP and DCP), retinal sensitivity (RS), amplitude and implicit time of P1 were studied at 13 points located at different distances from the fixation point were evaluated. Data were analyzed in the projection of the hole, intraretinal cystic changes (ICC), neuroepithelial detachment (NED) and intact retina before surgical treatment, 7 days, and 3 months after. Results. In the area of hole, ICC, and NED, in comparison with intact areas of the retina, a significant decrease in RS, an increase in implicit time and a decrease in amplitude of P1, and a decrease in capillary density in the SCP and DCP were revealed. Functional restoration of the retina with an increase in its perfusion was noted 3 months after the surgery. The correlation was found between postoperative changes in RS and changes in capillary density in the SCP in the projection of NED (R=0.32, p=0.001) and ICC (R=0.19, p=0.001), as well as in the DCP in the projection of NED and ICC (R=0.31, p=0.001). The change in the amplitude P1 in the postoperative period significantly correlated with the change in perfusion in the SCP in the projection of the NED (R=0.38, p=0.001) and the hole area (R=0.31, p=0.001), as well as in the DCP in the projection of the ICC (R=0.31, p=0.01) and in the area of NED (R=0.28, p=0.001). Conclusion. Thus, when using a multimodal topographically oriented approach, a relationship was found in the postoperative period of changes in functional parameters at various points in the macular area with changes in local perfusion at the level of both SCP and DCP, while the relationship is most significant in the projection of NED along the tear edge and in the areas of ICC. Key words: full-thickness macular hole (FTMH), microperimetry, multifocal electroretinography, multimodal imaging, optical coherence tomography, optical coherence tomography-angiography

Sitagliptin therapy improves myocardial perfusion and arteriolar collateralization in chronically ischemic myocardium: A pilot study.

Dipeptidyl peptidase 4 inhibitors (DPP4i) may be cardioprotective based on several small animal and clinical studies, though randomized control trials have demonstrated limited benefit. Given these discrepant findings, the role of these agents in chronic myocardial disease, particularly in the absence of diabetes, is still poorly understood. The purpose of this study was to determine the effects of sitagliptin, a DPP4i, on myocardial perfusion and microvessel density in a clinically relevant large animal model of chronic myocardial ischemia. Normoglycemic Yorkshire swine underwent ameroid constrictor placement to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (CON, n = 8) or 100 mg oral sitagliptin (SIT) daily (n = 5). Treatment continued for 5 weeks, followed by hemodynamic measurements, euthanasia, and tissue harvest of ischemic myocardium. There were no significant differences in myocardial function between CON and SIT as measured by stroke work (p > 0.5), cardiac output (p = 0.22), and end-systolic elastance (p = 0.17). SIT was associated with increased absolute blood flow at rest (17% increase, IQR 12-62, p = 0.045) and during pacing (89% increase, IQR 83-105, p = 0.002). SIT was also associated with improved arteriolar density (p = 0.045) compared with CON, without changes in capillary density (p = 0.72). SIT was associated with increased expression of pro-arteriogenic markers MCP-1 (p = 0.003), TGFß (p = 0.03), FGFR1 (p = 0.002), and ICAM-1 (p = 0.03), with a trend toward an increase in the ratio of phosphorylated/active PLCγ1 to total PLCγ1 (p = 0.11) compared with CON. In conclusion, in chronically ischemic myocardium, sitagliptin improves myocardial perfusion and arteriolar collateralization via the activation of pro-arteriogenic signaling pathways.

Sex differences in the development of coronary microvascular diseases in type-2 diabetes: possible role of gap junction protein connexin-40

Type-2 diabetes (T2D) increases the risk of cardiovascular diseases 2-4 folds in both sexes compared to non-diabetic individuals. However, more than 50% of female patients who experience chest pain have coronary microvascular disease (CMD) instead of obstructive CAD. On the other hand, 20% of men with chest pain have CMD. CMD is characterized by reduced coronary flow reserve, and coronary flow is regulated by the change in capillary density and vessel diameter. Gap junction protein connexin-40 (Cx40) plays a significant role in coronary microvascular function by controlling endothelium-dependent relaxation (EDR), cardiac endothelial cell (CEC) migration and capillary density. We hypothesized that T2D differentially affects the CX-40 expression and function in male and female coronary artery (CA) and causes CMD. The objective of this study is to identify the molecular mechanisms underlining the development of T2D-induced CMD in male and female mice.T2D mice were generated by a combination of high-fat diet feeding and a low-dose of streptozotocin (75 mg/kg, i.p.). The oral glucose tolerance was conducted at 4-, 8-, 12-, and 16 weeks after diabetes induction. Coronary flow velocity reserve (CFVR) was used to assess coronary microvascular function in mice. Coronary endothelial function was determined by 1) capillary density measurement in the left ventricle and 2) isometric tension experiment in small CAs (3rd order). CECs from male and female mice were isolated to conduct molecular biological experiments.There was no significant difference in CFVR and capillary density between control male and female mice. However, T2D mice of both sexes showed significant differences in the properties of EDR, CFVR and capillary density. T2D male mice exhibited a significant attenuation of EDR accompanied by impaired endothelium-derived nitric oxide(EDNO)-dependent relaxation and endothelium-dependent hyperpolarization (EDH)-mediated relaxation. On the contrary, there is no difference in EDR between control and diabetic female mice. Capillary density was reduced in T2D mice of both sexes compared to the respective controls. Our RNA sequencing data in CECs revealed that Cx40 is one of the genes which contributes to diabetes-mediated CMD. Systemic Cx40-KO male mice showed reduced EDR, EDH-mediated relaxation and capillary density compared to wild type control. T2D reduced the expression of Cx40 and overexpression of Cx40 restored EDR in CAs and increased capillary density in T2D male mice.T2D impaired coronary microvascular function in both sexes. However, the cause of reduced CFVR was different between diabetic male and female mice. In T2D females, capillary rarefaction was a primary cause of reduced CFVR. In contrast, attenuated EDNO- and EDH-mediated relaxation, reduced capillary density and downregulation of Cx40 contributed to decreased CFVR in T2D male mice. Future studies are required to establish the role of Cx40 in the development of CMD in T2D females. Supported by NIH R01HL142214 and DOD W81XWH2110472 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Video-capillaroscopy, a promising tool for the clinical evaluation of patients with chronic venous insufficiency.

The cutaneous microangiopathy plays a key role in the development of the skin clinical lesions of venous insufficiency. Capillaroscopy allows a non-invasive observation of the superficial skin capillaries of the lower leg, which have previously been shown to be altered in patients with advanced venous disease. As it is now available in a friendly, easy to handle way through modern video devices, we report our findings in a short series of patients with C3-C5 chronic venous disorders using this technique. A total of 21 patients with venous insufficiency (C3-C5 on at least one leg) underwent a capillaroscopic examination of both legs and pictures recorded from the sites of the most severe venous skin lesions. This was performed with a CapXview handheld video-capillaroscope (×100 magnification), allowing easy manual measurement of maximum capillary bulk diameter and capillary density. Dramatic changes in capillary density, size, and shape were easily observed at the site of the venous skin lesions. A significant negative linear relationship was found between capillary density and the "C" classes (r = -0.45; P < 0.001). A significant negative correlation was also found between capillary density and bulk diameter (r = -0.52; P < 0.001). The area under the ROC curve for the mathematical prediction of venous skin changes by capillary density was 0.842, which shows the strength of the link between the microvascular and the clinical status. Video-capillaroscopy allows a direct observation of the cutaneous venous microangiopathy and provides the possibility to measure capillary density which allows its quantification. This simple to use technique shows the potential for a more precise follow-up and treatment evaluation of the cutaneous consequences of venous disease, which remains to be further investigated.

Depletion of vascular adaptive mechanisms in hypertension-induced injury of the heart and kidney.

Vascular endothelial growth factor (VEGF) is a signalling protein of critical importance for angiogenesis. In an effort to better understand its significance in hypertension-induced injury of the heart and kidney we aimed at studying the changes in its expression in an experimental model and correlated it with capillary density in the myocardium and the renal parenchyma. We used two age groups of spontaneously hypertensive rats (6- and 12-month-old), indicative of early and advanced hypertension. VEGF expression was assessed and a semi-quantitative analysis of its immunoreactivity was conducted. Changes in capillary density in the myocardium and kidney were assessed for statistical significance and correlations with VEGF expression were established. We reported stronger VEGF expression in animals with early compared to advanced hypertension in all examined structures. Capillary density decreased significantly at age 12 months compared to 6 months and was significant in all examined structures. A positive correlation was established between capillary density and the expression of VEGF. These findings underscore the key significance of VEGF for compensatory angiogenesis and suggest that a statistically significant depletion of these vascular adaptive mechanisms is a major aspect in the cascade of hypertension-induced injury of the heart and kidney (Tab. 3, Fig. 26, Ref. 47).

Nailfold Capillaroscopy in Early Stages of Mixed Connective Tissue Disease in a Sample of Egyptian Patients

Introduction: Mixed connective tissue disease (MCTD) is a systemic autoimmune disease with a high titer of anti-U1 small nuclear ribonucleoprotein particles and a number of clinical pictures, mainly Raynaud's phenomenon. Nailfold capillaroscopy (NFC) is a noninvasive diagnostic tool for patients with different connective tissue diseases that permit detection of local microvascular changes that correlate with systemic vascular involvement. Aim of the Study: The aim of this study was to compare the results of NFC in patients with systemic sclerosis (SSc) and MCTD to determine the chief characteristics of skin microangiopathy in early MCTD and attempt to describe a characteristic MCTD pattern in Egyptian patients. Methodology: This cross-sectional study included forty patients diagnosed with MCTD according to Alarcón-Segovia and Villareal criteria and twenty patients with confirmed systemic sclerosis according to the American College of Rheumatology and the European League against Rheumatism classification criteria for Systemic Sclerosis. Nailfold examination for the study subjects was performed describing architectural derangement, capillary density changes, mega capillary and enlarged loops, microhemorrhages, and angiogenesis. Results: Of the sixty patients studied, 49 (81.7%) patients were females and 11 were males with a mean age of 31 years with a median of 29.5 and range 16–52 years. Three of the twenty patients diagnosed with systemic sclerosis had arthritis. Out of sixty patients, 53.3% had thickened skin, 19 patients exhibited puffy fingers, six patients showed rash, and none had swollen joints. The skin was significantly thicker in systemic sclerosis patients (85%) compared to 37.5% in the MCTD population. Patients presented with various features, the most common of which was fatigue (26.7%) and myositis (23% of patients). There is a significant negative correlation of −0.508 (P = 0.022) between the enlargement scores and illness duration in systemic sclerosis patients. Those patients also exhibited a statistically significant positive correlation of 0.520 (P = 0.019) between hemorrhage score and the number of tender joints. Alternatively, patients diagnosed with MCTD exhibited a significant positive correlation between the architectural changes scores of their joints and both the duration of their illness (0.347; P = 0.028) and the number of swollen joints (0.424; P = 0.006). MCTD patients also showed a significant correlation of 0.423 (P = 0.007) between their hemorrhage scores and their age at the time of the study. Conclusion: In this study, the results obtained were qualitatively satisfactory for clear delineation of the nailfold capillaries features in MCTD. Therefore, it aids in the recognition of alternations in nailfold capillaries making an early prediction of course of illness in MCTD patients possible and suggests a potential ability to differentiate from early SSc, thus helps in preventing morbidities and sequelae of the disease.

Retinal Capillary Damage Is Already Evident in Patients With Hypertension and Prediabetes and Associated With HbA1c Levels in the Nondiabetic Range.

We analyzed whether any change in capillary density in the retinal circulation could be detected in patients with hypertension in the prediabetic stage. In a cross-sectional analysis, we assessed capillary density in the foveal (CDF) and parafoveal retinal areas using optical coherence tomography-angiography in 62 patients with hypertension and normal glucose metabolism and 40 patients with hypertension and prediabetes. The CDF was lower in patients with prediabetes than in those with normal glucose metabolism. Moreover, we found a correlation between CDF and HbA1c and glucose levels for the entire cohort. In patients with HbA1c <6.5% (48 mmol/mol), CDF was lower in patients with HOMA for insulin resistance (HOMA-IR) ≥2.5 than in patients with HOMA-IR <2.5. Patients with hypertension and prediabetes display retinal capillary changes, and an association with markers of glucose metabolism exists, even within a nondiabetic HbA1c range.

Association of Neuroretinal Thinning and Microvascular Changes with Hypertension in an Older Population in Southern Italy

Background: Retinal microvasculature assessment at capillary level may potentially aid the evaluation of early microvascular changes due to hypertension. We aimed to investigate associations between the measures obtained using optical coherence tomography (OCT) and OCT-angiography (OCT-A) and hypertension, in a southern Italian older population. Methods: We performed a cross-sectional analysis from a population-based study on 731 participants aged 65 years+ subdivided into two groups according to the presence or absence of blood hypertension without hypertensive retinopathy. The average thickness of the ganglion cell complex (GCC) and the retinal nerve fiber layer (RNFL) were measured. The foveal avascular zone area, vascular density (VD) at the macular site and of the optic nerve head (ONH) and radial peripapillary capillary (RPC) plexi were evaluated. Logistic regression was applied to assess the association of ocular measurements with hypertension. Results: GCC thickness was inversely associated with hypertension (odds ratio (OR): 0.98, 95% confidence interval (CI): 0.97–1). A rarefaction of VD of the ONH plexus at the inferior temporal sector (OR: 0.95, 95% CI: 0.91–0.99) and, conversely, a higher VD of the ONH and RPC plexi inside optic disc (OR: 1.07, 95% CI: 1.04–1.10; OR: 1.04, 95% CI: 1.02–1.06, respectively) were significantly associated with hypertension. Conclusion: A neuroretinal thinning involving GCC and a change in capillary density at the peripapillary network were related to the hypertension in older patients without hypertensive retinopathy. Assessing peripapillary retinal microvasculature using OCT-A may be a useful non-invasive approach to detect early microvascular changes due to hypertension.

Longitudinal Macular Retinal and Choroidal Microvasculature Changes in High Myopia.

PurposeThe purpose of this study was to determine the longitudinal changes in macular retinal and choroidal microvasculature in normal healthy and highly myopic eyes.MethodsSeventy-one eyes, including 32 eyes with high myopia and 39 healthy control eyes, followed for at least 12 months and examined using optical coherence tomography angiography imaging in at least 3 visits, were included in this study. Fovea-centered 6 × 6 mm scans were performed to measure capillary density (CD) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC). The rates of CD changes in both groups were estimated using a linear mixed model.ResultsOver a mean 14-month follow-up period, highly myopic eyes exhibited a faster rate of whole image CD (wiCD) loss (−1.44%/year vs. −0.11%/year, P = 0.001) and CD loss in the outer ring of the DCP (−1.67%/year vs. –0.14%/year, P < 0.001) than healthy eyes. In multivariate regression analysis, baseline axial length (AL) was negatively correlated with the rate of wiCD loss (estimate = −0.27, 95% confidence interval [CI] = −0.48 to −0.06, P = 0.012) and CD loss in the outer ring (estimate = −0.33, 95% CI = −0.56 to −0.11, P = 0.005), of the DCP. The CD reduction rates in the SCP and CC were comparable in both groups (all P values > 0.05).ConclusionsThe rate of CD loss in the DCP is significantly faster in highly myopic eyes than in healthy eyes and is related to baseline AL. The CD in the outer ring reduces faster in eyes with longer baseline AL.

Cell - Vessel Mismatch in Glaucoma: Correlation of Ganglion Cell Layer Soma and Capillary Densities.

PurposeThe purpose of this study was to characterize the relationship between retinal ganglion cell layer (GCL) soma density and capillary density in glaucomatous eyes.MethodsSix glaucoma subjects with known hemifield defects and 6 age-matched controls were imaged with adaptive optics – optical coherence tomography (AO-OCT) at 6 locations: 3 degrees, 6 degrees, and 12 degrees temporal to the fovea above and below the midline. GCL soma density and capillary density were measured at each location. Coefficients of determination (pseudo R2) and slopes between GCL soma and capillary density were determined from mixed-effects regressions and were compared between glaucoma and control subjects, between more and less affected hemifield in subjects with glaucoma, and between subjects with early and moderate glaucoma, both in a local, bivariate model and then a global, multivariable model controlling for eccentricity and soma size.ResultsThe global correlation between GCL soma and capillary density was stronger in control versus subjects with glaucoma (R2 = 0.59 vs. 0.22), less versus more affected hemifields (R2 = 0.55 vs. 0.01), and subjects with early versus moderate glaucoma subjects (R2 = 0.44 vs. 0.18). When controlling for eccentricity and soma size, we noted an inverse soma-capillary density local relationship in subjects with glaucoma (−388 ± 190 cells/mm2 per 1% change in capillary density, P = 0.046) and more affected hemifields (−602 ± 257 cells/mm2 per 1% change in capillary density, P = 0.03).ConclusionsAn inverted soma-capillary density local relationship in areas affected by glaucoma potentially explains weaker global correlations observed between GCL soma and capillary density, suggesting cell–vessel mismatch is associated with the disease.

Use of ultra-wide field retinal imaging and optical coherence tomography angiography in the diagnosis of incomplete Susac syndrome.

To describe clinical findings through ultra-wide field (UWF) images and optical coherence tomography angiography (OCT-A), in Susac's syndrome (SS). SS patients were retrospectively analyzed in a single center. Clinical features, ultra-wide-field retinographies (UWF-PR), UWF fluorescein angiographies (UWF-FA), and optical coherence tomography angiography & en face (OCT-A/EF) were reviewed. Twelve eyes from six patients with a mean follow-up of 35.66 months ± SD 36.88 were included. UWF-PR showed areas of retinal whitening and cotton-wool spots in all the eyes after acute attack. Segmentary mid peripheral arteriolitis could be observed in five eyes by UWF-FA in acute and convalescent stages. OCT-A revealed capillary density changes in all of the affected eyes. During the acute phase there was a well-preserved superficial capillary network, while deep retinal plexus showed a lower density in the affected areas. OCT-A/EF revealed deep retinal plexus drop-out and surrounding edematous retina in acute attacks, becoming atrophic over time. Conversely, superficial plexus was much less affected. Perifoveal reperfusion was seen in seven eyes after the acute attack. UWF-PR/FA and OCT-A/EF might be helpful to stablish an early diagnosis and to monitor SS progression.

Enhanced notch signaling modulates unproductive revascularization in response to nitric oxide-angiopoietin signaling in a mouse model of peripheral ischemia.

IntroductionArteriolargenesis can be induced by concomitant stimulation of nitric Oxide (NO)‐Angiopoietin receptor (Tie)‐Vascular Endothelial Growth Factor (VEGF) signaling in the rat mesentery angiogenesis assay. We hypothesized that the same combination of exogenously added growth factors would also have a positive impact on arteriolargenesis and, consequently, the recovery of blood flow in a model of unilateral hindlimb ischemia.Results and MethodsNO‐Tie mice had faster blood flow recovery compared to control mice, as assessed by laser speckle imaging. There was no change in capillary density within the ischemic muscles, but arteriole density was higher in NO‐Tie mice. Given the previously documented beneficial effect of VEGF signaling, we tested whether NO‐Tie‐VEGF mice would show further improvement. Surprisingly, these mice recovered no differently from control, arteriole density was similar and capillary density was lower. Dll4 is a driver of arterial specification, so we hypothesized that Notch1 expression would be involved in arteriolargenesis. There was a significant upregulation of Notch1 transcripts in NO‐Tie‐VEGF compared with NO‐Tie mice. Using soluble Dll4 (sDll4), we stimulated Notch signaling in the ischemic muscles of mice. NO‐Tie‐sDll4 mice had significantly increased capillary and arteriole densities, but impaired blood flow recovery.ConclusionThese results suggest that Dll4 activation early on in revascularization can lead to unproductive angiogenesis and arteriolargenesis, despite increased vascular densities. These results suggest spatial and temporal balance of growth factors needs to be perfected for ideal functional and anatomical revascularisation.

Early Life Microcirculatory Plasticity and Blood Pressure Changes in Low Birth Weight Infants Born to Normotensive Mothers: A Cohort Study.

BACKGROUNDCapillary rarefaction (CR) is an established hallmark of essential hypertension (EH). The aim of this study was to examine early changes in capillary density (CD) and blood pressure (BP) in low birth weight (LBW) infants who are at risk of developing EH in later life.METHODSWe studied 77 LBW infants and 284 normal birth weight (NBW) infants, all born to mothers with normotension, in a longitudinal multicenter study. Intravital capillaroscopy was used to measure functional basal capillary density (BCD) and maximal capillary density (MCD) at birth, 3, 6, and 12 months.RESULTSWe found that LBW infants, born preterm and at term, had a significantly higher CD at birth, then underwent significant CR in the 1st 3 months culminating in a CD similar to that seen in NBW infants. NBW infants showed a gradual reduction in CD between birth and 12 months. Non-Caucasian ethnicity and preterm birth were significant predictors of a higher CD at birth. Systolic BP in NBW infants increased significantly from birth to 3 months, and we identified a significant negative correlation between systolic BP and MCD.CONCLUSIONSThis study has identified a process of early “accelerated capillary remodeling” in LBW infants, which corrects their higher CD at birth. This remodeling is unlikely to explain the CR seen in adult individuals with, or at risk of developing EH. Further follow-up studies are required to determine the timing and mechanisms involved in CR, which is likely to occur after the 1st year of life but before early adulthood.

Gender-specific effects of Notch3 in cardiac phenotype after moderate physical training

Studies in mice have shown that the Notch3 protein plays a major role in the functional and structural plasticity of resistance arteries, angiogenesis, and contributes to the adaptation of these vessels to variations in loading conditions. Our aim was to determine whether gender is a factor of the cardiac phenotype of Notch3 KO mice in the basal state and in response to a volume overload. Two-month-old male and female C57Bl/6 J WT and KO Notch3 mice were used in a moderate training protocol on treadmill with increasing speed, in order to mimic the effort induced during cardiac rehabilitation. In basal conditions, KO mice are characterized by a low expression of VEGFR2 mRNA, leading to an arteriolar rarefaction ( P < 0.0002) without changes in capillary density regardless of gender. This results to a fibrosis in KO mice. However, gender differences are observed since males display cardiac hypertrophy ( P < 0.0001) while females have a decreased shortening fraction ( P < 0.0001). In training conditions, expression of sFlt1 mRNA increased in female Notch3 KO mice. Physical training increased the capillary density only in WT males ( P < 0.0332) whereas, it reduced the capillary density ( P < 0.0021) and induced cardiac fibrosis ( P < 0.0021) in Notch3 KO females. In addition, physical training reversed cardiac hypertrophy ( P < 0.0332) in male Notch3 KO, but has no major effect in the cardiac function of female Notch3 KO. This work highlights for the first time the gender-specific effects of Notch3 in the heart phenotype under control conditions and after moderate physical training.

Comparación de la densidad capilar parafoveal entre sujetos sanos y diabéticos con y sin retinopatía

Parafoveal capillary density changes have not been characterized in type 2 diabetics without retinopathy. To compare parafoveal capillary density between healthy subjects, and diabetics with and without retinopathy. Observational, prospective, transversal and comparative study; subjects without diabetes (group 1), diabetics without retinopathy (group 2), with retinopathy (group 3) and with diabetic macular edema (group 4), without macular ischemia, were included. The study variable was parafoveal capillary density, and the predictor variables were the measures of the foveal avascular zone, retinal thickness and the group. The variables were compared between groups using Kruskal-Wallis and Spearman's Rho tests. One hundred and forty eyes were evaluated; parafoveal capillary density was higher in group 1 than in the rest (p < 0.05). Area, perimeter and diameter of the foveal avascular zone were higher in group 3. A positive correlation existed a positive between parafoveal capillary density and central field thickness in groups 1, 2 and 3. Parafoveal capillary density decreases as diabetes-induced damage increase; a reduction may exist in diabetics without retinopathy and normal retinal thickness and foveal avascular zone are normal. The clinical impact of this finding requires further evaluation.

Hit hard and early: analysing the effects of high-dose methylprednisolone on nailfold capillary changes and biomarkers in very early systemic sclerosis: study protocol for a 12-week randomised controlled trial

BackgroundMounting evidence indicates that inflammatory mechanisms drive systemic sclerosis (SSc) vasculopathy and fibrosis, especially early in the disease. Therefore, patients with very early SSc could benefit from early treatments targeting inflammation. Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. Several studies have demonstrated a mixed response to treatment with glucocorticoids in SSc, probably because it is seldom initiated at very early stages of the disease. We hypothesise that by inhibiting the inflammatory process driving SSc disease progression, glucocorticoid treatments will induce remission in patients with very early SSc.Methods/designThis study is a 12-week, randomised, double-blind, placebo-controlled trial analysing the effects of high-dose intravenous methylprednisolone in very early SSc. Thirty patients who fulfil the criteria for very early SSc will be randomly assigned in a 2:1 ratio to receive either intravenous methylprednisolone or a placebo on three consecutive days over three consecutive months. In this study, the primary endpoint will be the change in capillary density between the baseline and after 12 weeks of treatment. The secondary outcomes of this study are a change in selected biomarkers, other changes in the nailfold capillaries, signs of established SSc and changes in physical function, general health and utilities, as reported through questionnaires.DiscussionThis trial is the first aiming to treat very early SSc and is promising because it targets the very early stages of the disease process by using an inexpensive and relatively safe treatment known to be highly effective against inflammation. The use of vasculopathy and inflammatory biomarkers as well as clinical signs and symptoms as the endpoints in our study enables us to meet the patient need for markers of disease activity. If it is possible to prevent clinically significant disease in patients with very early SSc by using a safe treatment, this will cause a paradigm shift in scleroderma care and research.Trial registrationClinicalTrials.gov Identifier: NCT03059979. Registered on 20 February 2017.