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The angiogenic mechanism and therapeutic potential of PDGF-CC, a recently discovered member of the VEGF/PDGF superfamily, remain incompletely characterized. Here we report that PDGF-CC mobilized endothelial progenitor cells in ischemic conditions; induced differentiation of bone marrow cells into ECs; and stimulated migration of ECs. Furthermore, PDGF-CC induced the differentiation of bone marrow cells into smooth muscle cells and stimulated their growth during vessel sprouting. Moreover, delivery of PDGF-CC enhanced postischemic revascularization of the heart and limb. Modulating the activity of PDGF-CC may provide novel opportunities for treating ischemic diseases.

Background The endothelial glycocalyx (eGC) covers the luminal surface of the vascular endothelium and plays an important protective role in systemic inflammatory states and particularly in sepsis. Its breakdown leads to capillary leak and organ dysfunction. Moreover, sepsis-induced alterations of sublingual microcirculation are associated with a worse clinical outcome. The present study was performed to investigate the associations between eGC dimensions and established parameters of microcirculation dysfunction in sepsis. Methods This observational, prospective, cross-sectional study included 40 participants, of which 30 critically ill septic patients were recruited from intensive care units of a university hospital and 10 healthy volunteers served as controls. The established microcirculation parameters were obtained sublingually and analyzed according to the current recommendations. In addition, the perfused boundary region (PBR), an inverse parameter of the eGC dimensions, was measured sublingually, using novel data acquisition and analysis software (GlycoCheck™). Moreover, we exposed living endothelial cells to 5% serum from a subgroup of study participants, and the delta eGC breakdown, measured with atomic force microscopy (AFM), was correlated with the paired PBR values. Results In septic patients, sublingual microcirculation was impaired, as indicated by a reduced microvascular flow index (MFI) and a reduced proportion of perfused vessels (PPV) compared to those in healthy controls (MFI, 2.93 vs 2.74, p  = 0.002; PPV, 98.53 vs 92.58, p  = 0.0004). PBR values were significantly higher in septic patients compared to those in healthy controls, indicating damage of the eGC (2.04 vs 2.34, p  < 0.0001). The in vitro AFM data correlated exceptionally well with paired PBR values obtained at the bedside (rs = − 0.94, p  = 0.02). Both PBR values and microcirculation parameters correlated well with the markers of critical illness. Interestingly, no association was observed between the PBR values and established microcirculation parameters. Conclusion Our findings suggest that eGC damage can occur independently of microcirculatory impairment as measured by classical consensus parameters. Further studies in critically ill patients are needed to unravel the relationship of glycocalyx damage and microvascular impairment, as well as their prognostic and therapeutic importance in sepsis. Trial registration Retrospectively registered: Clinicaltrials.gov, NCT03960307

Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve–induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.

Cardiovascular disease (CVD) is the leading cause of mortality in people with type 2 diabetes mellitus (T2DM), yet a significant proportion of the disease burden cannot be accounted for by conventional cardiovascular risk factors. Hypertension occurs in majority of people with T2DM, which is substantially more frequent than would be anticipated based on general population samples. The impact of hypertension is considerably higher in people with diabetes than it is in the general population, suggesting either an increased sensitivity to its effect or a confounding underlying aetiopathogenic mechanism of hypertension associated with CVD within diabetes. In this contribution, we aim to review the changes observed in the vascular tree in people with T2DM compared to the general population, the effects of established anti-diabetes drugs on microvascular outcomes, and explore the hypotheses to account for common causalities of the increased prevalence of CVD and hypertension in people with T2DM.

Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles of inflammation and endothelial dysfunction been properly assessed. Although still incompletely understood, current knowledge of the pathophysiological mechanisms of CVD reveals several potential targets and strategies for therapeutic intervention, some of which are addressable by currently available venoactive drugs. The roles of these drugs in the clinical improvement of venous tone and contractility, reduction of edema and inflammation, as well as in improved microcirculation and venous ulcer healing have been studied extensively, with favorable results reported in the literature. Here, we aim to review these pathophysiological mechanisms and their implications regarding currently available venoactive drug therapies.

Catecholamines are used to increase cardiac output and blood pressure, aiming ultimately at restoring/improving tissue perfusion. While intuitive in its concept, this approach nevertheless implies to be effective that regional organ perfusion would increase in parallel to cardiac output or perfusion pressure and that the catecholamine does not have negative effects on the microcirculation. Inotropic agents may be considered in some conditions, but it requires prior optimization of cardiac preload. Alternative approaches would be either to minimize exposure to vasopressors, tolerating hypotension and trying to prioritize perfusion but this may be valid as long as perfusion of the organ is preserved, or to combine moderate doses of vasopressors to vasodilatory agents, especially if these are predominantly acting on the microcirculation. In this review, we will discuss the pros and cons of the use of catecholamines and alternative agents for improving tissue perfusion in septic shock.

Acute elevations in blood glucose can influence microvascular function and autonomic nervous system (ANS) reactivity, both implicated in cardiometabolic risk. We assessed the effects of oral glucose tolerance test (OGTT) on microvascular and ANS physiological responses in healthy young individuals. Using laser Doppler flowmetry (LDF), we measured basal skin microcirculatory blood flow and responses to post-occlusive reactive hyperemia, iontophoresis of acetylcholine (ACh), and sodium nitroprusside (SNP) in 28 participants before and 45 and 120 min after OGTT or water loading. LDF spectral components were analyzed using wavelet analysis (WA). ANS reactivity was evaluated from electrocardiogram recordings by analyzing heart rate variability (HRV). OGTT caused time-dependent changes in microvascular and HRV parameters. Endothelial nitric oxide-independent vasodilation transiently decreased during SNP response ( p  = 0.014), while myogenic component transiently increased ( p  = 0.029; two-way repeated measures ANOVA), with no significant change in the endothelial nitric oxide-dependent component. HRV measures RMSSD ( p  = 0.009) and SDNN ( p  = 0.008) decreased. Oral glucose loading affects microcirculation in healthy individuals, likely through modulation of endothelial nitric oxide-independent signaling, vascular smooth muscle responsiveness, and ANS reactivity. WA may offer a sensitive method for detecting microvascular dysfunction associated with physiological changes following oral glucose loading.

We recently found evidence of an angiotensin-generating system in pancreatic islets. The present study investigated the effect of endogenously produced angiotensin II on microcirculation and function in transplanted islets. Losartan, an angiotensin II type 1 receptor inhibitor, was administered either acute intravenously to mice with 4-week-old islet renal subcapsular transplants, or added to the drinking water for the final 14 days or throughout the 4-week post-transplantation period. The graft-bearing kidney was, in some cases, dissected out and perfused in vitro to evaluate the effect of angiotensin II and losartan on glucose-stimulated insulin release from the grafts. Losartan treatment throughout the 4-week post-transplantation period had negative effects on islet revascularisation as well as on islet graft insulin release. However, administration of losartan, either intravenously or orally, after the formation of a new vascular network, improved islet graft blood perfusion. PO2 in the islet transplants was also effectively improved by the losartan treatment. Graft perfusion experiments showed a markedly better first phase of glucose-stimulated insulin release in transplanted islets when exposed to losartan. In contrast, acute administration of angiotensin II decreased islet graft blood flow, PO2 and glucose-stimulated insulin release. This study shows that inhibition of the islet reninangiotensin system may be a feasible strategy to increase the blood perfusion, PO2 and function within islet grafts. Such treatment should not be initiated, however, before the islet vascular system has been formed.

Caffeine is being increasingly used in cosmetics due to its high biological activity and ability to penetrate the skin barrier. This alkaloid is frequently used as a hydrophilic model substance in human and animal skin penetration as well as different synthetic membrane using Franz diffusion cell experiments. The commercially available topical formulations of caffeine normally contain 3% caffeine. As for a cosmetic purpose, caffeine is used as an active compound in anti-cellulite products because it prevents excessive accumulation of fat in cells. This alkaloid stimulates the degradation of fats during lipolysis through inhibition of the phosphodiesterase activity. Caffeine has potent antioxidant properties. It helps protect cells against the UV radiation and slows down the process of photoaging of the skin. Moreover, caffeine contained in cosmetics increases the microcirculation of blood in the skin and also stimulates the growth of hair through inhibition of the 5-α-reductase activity.

Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by severe intestinal necrosis and for which breast milk represents the most effective protective strategy. Previous studies have revealed a critical role for the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in NEC development through its induction of mucosal injury, yet the reasons for which intestinal ischemia in NEC occurs in the first place remain unknown. We hypothesize that TLR4 signaling within the endothelium plays an essential role in NEC development by regulating perfusion to the small intestine via the vasodilatory molecule endothelial nitric oxide synthase (eNOS). Using a unique mouse system in which we selectively deleted TLR4 from the endothelium, we now show that endothelial TLR4 activation is required for NEC development and that endothelial TLR4 activation impairs intestinal perfusion without effects on other organs and reduces eNOS expression via activation of myeloid differentiation primary response gene 88. NEC severity was significantly increased in eNOS ⁻/⁻ mice and decreased upon administration of the phosphodiesterase inhibitor sildenafil, which augments eNOS function. Strikingly, compared with formula, human and mouse breast milk were enriched in sodium nitrate—a precursor for enteral generation of nitrite and nitric oxide—and repletion of formula with sodium nitrate/nitrite restored intestinal perfusion, reversed the deleterious effects of endothelial TLR4 signaling, and reduced NEC severity. These data identify that endothelial TLR4 critically regulates intestinal perfusion leading to NEC and reveal that the protective properties of breast milk involve enhanced intestinal microcirculatory integrity via augmentation of nitrate–nitrite–NO signaling.