Microvascular research最新文献

Purpose

The aim of this study was to investigate the microvascular changes in the retina and choroid in gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) and to compare the results with those of healthy pregnant subjects.

Methods

Twenty-nine pregnant subjects with coexisting GDM and PIH (group 1) and 36 healthy pregnant subjects (group 2) were enrolled in the study. All subjects were examined by optical coherence tomography (OCT) and angiography (OCTA). The retina, retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), choroidal thickness (CT), superficial capillary plexus (SCP), deep capillary plexus (DCP), choriocapillaris (CC) vascular density (VD), and foveal avascular zone (FAZ) were measured.

Results

We observed that the values of CT and VD were lower in group 1 than in group 2. No significant difference was found between groups in RT, FAZ area and CC VD. SCP and DCP VD values were higher in group 2 in all quadrants. We observed a significant increase in FAZ area and CC VD with increasing systolic blood pressure. No correlation was observed between diastolic blood pressure and FBS with other parameters. In group 1, FAZ area was significantly higher in the diet-treated group than in the insulin-treated group.

Conclusion

Monitoring and treatment of pregnant women with PIH and GDM is important because of the risks that may occur during pregnancy. We believe that changes in microvascular circulation can be detected noninvasively with OCTA, even in the absence of clinical or retinal findings.

Previous studies have shown that expression of the endothelial laminin receptor α6β4 integrin in the brain is uniquely restricted to arterioles. As exposure to chronic mild hypoxia (CMH, 8 % O₂) stimulates robust angiogenic and arteriogenic remodeling responses in the brain, the goal of this study was to determine how CMH influences cerebrovascular expression of the β4 integrin as well as its potential ligands, laminin 411 and 511, containing the α4 and α5 laminin subunits respectively, and then define how aging impacts this expression. We observed the following: (i) CMH launched a robust arteriogenic remodeling response both in the young (10 weeks) and aged (20 months) brain, correlating with an increased number of β4 integrin+ vessels, (ii) while the laminin α4 subunit is expressed evenly across all cerebral blood vessels, laminin α5 was highly expressed preferentially on β4 integrin+ arterioles, (iii) CMH-induced arteriolar remodeling was associated with strong downregulation of the laminin α4 subunit but no change in the laminin α5 subunit, (iv) in addition to its expression on arterioles, β4 integrin was also expressed at lower levels on capillaries specifically in white matter (WM) tracts but not in the grey matter (GM), and (v), these observations were consistent in both the brain and spinal cord, and age had no obvious impact. Taken together, our findings suggest that laminin 511 may be a specific ligand for α6β4 integrin and that dynamic switching of the laminin subunits α4 and α5 might play an instructive role in arteriogenic remodeling. Furthermore, β4 integrin expression differentiates WM from GM capillaries, highlighting a novel and important difference.

Aims

Protein kinase D (PKD), once considered an effector of protein kinase C (PKC), now plays many pathophysiological roles in various tissues. However, little is known about role of PKD in vascular function. We investigated the role of PKD in contraction of rat aorta and human aortic smooth muscle cells (HASMCs) and in haemodynamics in rats.

Methods and results

Isometric tension of rat aortic was measured to examine norepinephrine-induced contraction in the presence of PKD, PKC and Rho-kinase inhibitors. Phosphorylation of PKD1, myosin targeting subunit-1 (MYPT1), myosin light chain (MLC), CPI-17 and heat-shock protein 27 (HSP27), and actin polymerization were measured in the aorta. Phosphorylation of MYPT1 and MLC was also measured in HASMCs knocked down with specific siRNAs of PKD 1, 2 and 3. Intracellular calcium concentrations and cell shortening were measured in HASMCs.

Norepinephrine-induced aortic contraction was accompanied by increased phosphorylation of PKD1, MYPT1 and MLC and actin polymerization, all of which were attenuated with PKD inhibitor CRT0066101. PKD1 phosphorylation was not inhibited by PKC inhibitor, chelerythrine or Rho kinase inhibitor, fasudil. In HASMCs, the phosphorylation of MYPT1 and MLC was attenuated by PKD1, but not PKD2, 3 knockdown. In HASMCs, CRT0066101 inhibited norepinephrine-induced cell shortening without affecting calcium concentration. Administration of CRT0066101 decreased systemic vascular resistance and blood pressure without affecting cardiac output in rats.

Conclusions

PKD1 may play roles in aorta contraction and haemodynamics via phosphorylation of MYPT1 and actin polymerization in a calcium-independent manner.

Retinopathy of prematurity (ROP), a retinal disease that can occur in premature infants, can lead to severe visual impairment. In this study, we examined the preventive and therapeutic effects of mammalian target of rapamycin complex 1 (mTORC1) inhibition on abnormal retinal blood vessels in a rat model of ROP. To induce ROP-like vascular abnormalities, rats were subcutaneously treated with KRN633, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, on postnatal day 7 (P7) and P8. KRN633-treated (ROP) rats were treated subcutaneously with the mTORC1 inhibitor rapamycin according to preventive and therapeutic protocols, i.e., from P11 to P13 (P11–P13) and from P14 to P20 (P14–P20), respectively. To compare with the effects of VEGF inhibition, KRN633 was administered according to similar protocols. Changes in retinal vasculature, phosphorylated ribosomal protein S6 (pS6), a downstream indicator of mTORC1 activity, and the proliferative status of vascular cells were evaluated at P14 and P21 using immunohistochemistry. Rapamycin treatment from P11 to P13 prevented increases in arteriolar tortuosity, capillary density, and the number of proliferating vascular cells, and eliminated pS6 immunoreactivity in ROP rats. KRN633 treatment at P11 and P12 (P11/P12) also prevented the appearance of ROP-like retinal blood vessels. Rapamycin treatment from P14 to P20 failed to attenuate arteriolar tortuosity but prevented increases in capillary density and proliferating vascular cell number at the vascular front, but not at the central zone. KRN633 treatment from P14 to P20 significantly reduced abnormalities in the retinal vasculature; however, the effects were inferior to those of KRN633 treatment on P11/P12. These results suggest that activation of the mTORC1 pathway in proliferating endothelial cells contributes to the appearance and progression of ROP-like retinal blood vessels. Therefore, inhibition of mTORC1 may be a promising approach for selectively targeting abnormal retinal blood vessels in ROP.

Vascular impairment is closely related to increased mortality in chronic kidney disease (CKD). The objective of this study was to assess impairments in the regulation of peripheral microvascular perfusion in patients with CKD based on time-frequency spectral analysis of resting near-infrared spectroscopy (NIRS) signals. Total hemoglobin (tHb) concentration and tissue saturation index (TSI) signals were collected using NIRS for a continuous 5 mins at 10 Hz from the forearm of 55 participants (34 CKD including 5 with end-stage renal disease, and 21 age-matched control). Continuous wavelet transform-based spectral analysis was used to quantify the spectral amplitude within five pre-defined frequency intervals (I, 0.0095–0.021 Hz; II, 0.021–0.052 Hz; III, 0.052–0.145 Hz; IV, 0.145–0.6 Hz and V, 0.6–2.0 Hz), representing endothelial, neurogenic, myogenic, respiratory and heartbeat activity, respectively. CKD patients showed lower tHb average spectral amplitude within the neurogenic frequency interval compared with controls (p = 0.014), consistent with an increased sympathetic outflow observed in CKD. CKD patients also showed lower TSI average spectral amplitude within the endothelial frequency interval compared with controls (p = 0.046), consistent with a reduced endothelial function in CKD. These findings demonstrate the potential of wavelet analysis of NIRS to provide complementary information on peripheral microvascular regulation in CKD.

Objective

Type B aortic dissection (TBAD) and intramural aortic hematoma (IMH) are common manifestations of Acute Aortic Syndrome (AAS), exhibiting overlapping clinical features. The timely and accurate diagnosis and differentiation between TBAD and IMH are critical for appropriate management. Tumorigenicity 2 (sST2) and D-dimer have been shown to elevate levels in both TBAD and IMH, making them valuable as “rule-out” markers. Hence, we aimed to assess the diagnostic utility of sST2 and D-dimer in distinguishing TBAD from IMH.

Methods

In this retrospective study, we analyzed serum levels of sST2 and D-dimer in 182 AAS patients, comprising 90 TBAD cases, 92 IMH cases, and 90 non-AAS cases. Serial measurements were taken at 1 h, 6 h, 12 h, 24 h, and 72 h post-admission. Comparative analyses were conducted between TBAD and non-AAS cases, IMH and non-AAS cases, and TBAD and IMH cases. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic accuracy of sST2 and D-dimer in identifying TBAD or IMH cases.

Results

Both TBAD and IMH patients displayed elevated levels of sST2 and D-dimer compared to non-AAS cases. Notably, sST2 levels were significantly higher in TBAD patients than in IMH patients, whereas D-dimer levels exhibited moderate differences. TBAD patients tended to exhibit elevated levels of either sST2 or D-dimer, with a modest correlation between the two (Pearson correlation coefficient = 0.3614). In contrast, IMH patients showed elevations in both markers, with a positive correlation between them (Pearson correlation coefficient = 0.6814). The ROC analysis revealed that both sST2 (AUC, 0.657; 95 % CI, 0.552–0.753; cutoff value, 27.54 ng/ml) and D-dimer (AUC, 0.695; 95 % CI, 0.591–0.787, cutoff value, 1.215 ng/ml) demonstrated favorable diagnostic performance for TBAD. sST2 exhibited a sensitivity of 80.92 % and a specificity of 75.00 %, while D-dimer showed a sensitivity of 80.92 % and a specificity of 75.00 %. For the diagnosis of IMH, the combined assessment of sST2 and D-dimer (AUC, 0.674; 95 % CI, 0.599–0.768; sensitivity, 69.20 %; specificity, 80.00 %) proved effective.

Conclusions

Our results indicate that both sST2 and D-dimer show diagnostic potential for TBAD. Elevated levels of either serve as an indicator of TBAD onset. However, concurrent elevation of both markers seems to be indicative of IMH. The combination of increased sST2 and D-dimer levels demonstrates strong diagnostic performance in identifying IMH cases.

Vasomotion refers to the spontaneous oscillation of blood vessels within a frequency range of 0.01 to 1.6 Hz. Various disease states, including hypertension and diabetes, have been associated with alterations in vasomotion at the finger, indicating potential impairment of skin microcirculation. Due to the non-linear nature of human vasculature, the modification of vasomotion may vary across different locations for different diseases. In this study, Laser Doppler Flowmetry was used to measure blood flow motion at acupoints LU8, LU5, SP6, and PC3 among 49 participants with or without diabetes and/or hypertension. Fast Fourier Transformation was used to analyze noise type while Hilbert-Huang Transformation and wavelet analysis were applied to assess Signal Noise Ratio (SNR) results. Statistical analysis revealed that different acupoints exhibit distinct spectral characteristics of vasomotion not only among healthy individuals but also among patients with diabetes and/or hypertension. The results showed strong heterogeneity of vasomotion among blood vessels, indicating that the vasomotion measured at a certain point may not reflect the real status of microcirculation.

Stroke is the second leading cause of death globally and the major cause of long-term disability. Among the types of strokes, ischemic stroke, which occurs due to obstruction of blood vessels responsible for cerebral irrigation, is considered the most prevalent, accounting for approximately 86 % of all stroke cases. This interruption of blood supply leads to a critical pathophysiological mechanism, including oxidative stress and neuroinflammation which are responsible for structural alterations of the blood-brain barrier (BBB). The increased BBB permeability associated with cerebral ischemia-reperfusion may contribute to a worse outcome after stroke. Thus, this narrative review aims to update the pathophysiological mechanisms involved in the increase in BBB permeability and to list the possible therapeutic strategies.

Type 1 diabetes mellitus (T1DM) is predominantly managed using insulin replacement therapy, however, pancreatic microcirculatory disturbances play a critical role in T1DM pathogenesis, necessitating alternative therapies. This study aimed to investigate the protective effects of glycine supplementation on pancreatic microcirculation in T1DM. Streptozotocin-induced T1DM and glycine-supplemented mice (n = 6 per group) were used alongside control mice. Pancreatic microcirculatory profiles were determined using a laser Doppler blood perfusion monitoring system and wavelet transform spectral analysis. The T1DM group exhibited disorganized pancreatic microcirculatory oscillation. Glycine supplementation significantly restored regular biorhythmic contraction and relaxation, improving blood distribution patterns. Further-more, glycine reversed the lower amplitudes of endothelial oscillators in T1DM mice. Ultrastructural deterioration of islet microvascular endothelial cells (IMECs) and islet microvascular pericytes, including membrane and organelle damage, collagenous fiber proliferation, and reduced edema, was substantially reversed by glycine supplementation. Additionally, glycine supplementation inhibited the production of IL-6, TNF-α, IFN-γ, pro-MMP-9, and VEGF-A in T1DM, with no significant changes in energetic metabolism observed in glycine-supplemented IMECs. A statistically significant decrease in MDA levels accompanied by an increase in SOD levels was also observed with glycine supplementation. Notably, negative correlations emerged between inflammatory cytokines and microhemodynamic profiles. These findings suggest that glycine supplementation may offer a promising therapeutic approach for protecting against pancreatic microcirculatory dysfunction in T1DM.

Introduction

Arterial hypertension is a global healthcare burden that affects macrovascular and microvascular structure and function and can promote vascular end-organ damage. This study aimed 1) to evaluate differences in microvascular health between normotensive individuals and patients with arterial hypertension and 2) to assess the effects of short-term high-intensity interval training (HIIT) on microvascular health in the subgroup with arterial hypertension as add-on treatment to antihypertensive medication.

Methods

In the cross-sectional part, central retinal arteriolar (CRAE) and venular diameter equivalent (CRVE), arteriolar-to-venular diameter ratio (AVR), and retinal oxygen saturation (O₂-saturation) were investigated in 19 normotensive healthy controls (mean age 56 ± 7 years) and 41 patients with arterial hypertension (mean age 59 ± 7 years). In the subsequent randomized controlled trial (RCT), patients with arterial hypertension were randomized to an intervention group (HIIT 3×/week) or a control group that received standard physical activity recommendations after baseline assessment. Assessments of retinal vessel biomarkers and patients` characteristics were repeated after the intervention period of 8 weeks.

Results

In the cross-sectional part, individuals with normal blood pressure (BP) showed lower body mass index (BMI), body fat, 24 h systolic and diastolic BP, higher peak oxygen uptake, wider CRAE (174 ± 17 μm vs. 161 ± 17 μm, p = 0.009), and higher AVR (0.84 ± 0.05 vs. 0.79 ± 0.05, p = 0.003) compared to patients with hypertension. In the RCT, patients with arterial hypertension showed reduced BMI and fasting glucose levels after HIIT and control condition. In addition, the intervention group reduced body fat percentage (27.0 ± 5.5 vs. 25.8 ± 6.1, p = 0.023) and increased peak oxygen uptake (33.3 ± 5.7 vs. 36.7 ± 5.1, p < 0.001). No changes in BP were found in either group. The intervention group showed narrower CRVE (β −4.8 [95 % CI, −8.85, −0.81] p = 0.020) and higher AVR (0.03 [0.01, 0.04] p < 0.001) after eight weeks of HIIT compared to the control group. No statistically significant changes in retinal O₂-saturation were found in either group.

Conclusion

Short-term HIIT proved to be an effective treatment to ameliorate hypertension-induced retinal microvascular abnormalities in patients with hypertension. Retinal vessel diameters may prove to be a sensitive biomarker to quantify treatment efficacy at the microvascular level, at the earliest possible stage in patients with hypertension.