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PubMed2025

The effect of penile tourniquet and continuous artificial erection on penile erectile tissues: An experimental study.

INTRODUCTION: Penile tourniquet (PT) is known to cause ischemic injury, which worsens with prolonged application. Artificial erection (AE), formed by intracorporal saline injection mostly under PT, has been practiced for decades to evaluate penile curvature, yet its effect on erectile tissues has never been investigated. In this study, we examined a modified approach, continuous artificial erection (CAE), and investigated its effects on erectile tissues. OBJECTIVE: This study aims to investigate the histopathological and immunohistochemical effects of CAE on penile erectile tissues. STUDY DESIGN: Thirty-five rats were randomized into five groups. Four experiment groups received 20 or 40 min of isolated PT (20T and 40T) or PT with CAE (20T&E and 40T&E). CAE was achieved through continuous intracavernosal saline injection. Penectomy was performed three weeks post-procedure in the experiment groups and directly in the control group. Erectile tissue samples were evaluated using light microscopy for histopathological parameters including inflammation, neovascularization and fibrosis, and by immunohistochemistry. Endothelial function was assessed by eNOS and e-selectin staining, while ICAM-1 staining was used to assess chronic inflammation. RESULTS: 40T showed the highest levels of inflammation, fibrosis, and endothelial dysfunction. 20T had significantly less inflammation than 40T, with a non-significant increase in fibrosis and alteration of endothelial markers. 40T&E displayed the second-highest fibrosis rate (adjusted p > 0.05), while 20T&E showed complete absence of fibrosis. Both 40T&E and 20T&E preserved strong eNOS and e-selectin expression, identical to controls. ICAM-1 expression in 20T&E was also consistent with the control group. The most significant difference in erectile tissue damage was noted between 40T and 20T&E. CONCLUSION: This is the first study to evaluate the effects of AE on erectile tissues. Findings of this experimental model support that, CAE does not increase the tissue damage that is already caused by PT, but rather reduces it, likely through the washout of blood elements contributing to reperfusion injury. CAE possibly provides a protective effect on erectile tissues by preserving endothelial function, reducing inflammation and fibrosis, especially under 20 minutes of duration. These findings may support that AE maneuvers such as "artificial erection test" and CAE are potentially safe, while further studies are needed to assess the detailed effects of CAE.

Male↗
PubMed2026

Optimizing physical activity bouts to interrupt sedentary behaviour for cardiometabolic health: a systematic review and meta-analyses of randomized controlled trials.

AIMS: Chronic diseases such as type 2 diabetes mellitus and cardiovascular diseases are leading causes of mortality worldwide, with sedentary behaviour (SB) and physical inactivity recognized as major interrelated risk factors. Prolonged SB, particularly when combined with insufficient physical activity, adversely affects cardiometabolic health. This systematic review aimed to evaluate which characteristics of physical activity (PA) bouts, in terms of frequency, duration, and intensity, are associated with improvements in cardiometabolic outcomes. METHODS AND RESULTS: Studies assessing physical activity interventions compared with sedentary control conditions were included. Eligible studies involved adults aged 18-65 years, with or without cardiometabolic conditions. PubMed, Cochrane Central, Embase, and Web of Science were searched to February 2025. Random-effects models were used to calculate pooled standardized mean differences (SMD) with 95% confidence interval (CI). Subgroup and meta-regression analyses explored potential moderators. A total of 144 studies (247 intervention arms; 2216 participants) were included. Frequent PA bouts reduced blood glucose [SMD -0.22 (95% CI -0.27 to -0.16)]. Longer and/or more intense PA bouts decreased triglycerides [SMD -0.27 (-0.34 to -0.19)], with significant duration &#xd7; intensity interactions for glucose (P = 0.032) and triglycerides (P < 0.001). Moderate-to-vigorous PA bouts improved endothelial function [flow-mediated dilation SMD 0.88 (0.47-2.24); shear rate SMD 0.54 (0.31-0.78)]. PA bouts also lowered insulin [SMD -0.26 (-0.32 to -0.19)], systolic BP [SMD -0.29 (-0.39 to -0.19)], and diastolic BP [SMD -0.16 (-0.26 to -0.05)]. CONCLUSION: In acute experimental settings, glucose regulation appears to benefit more from frequent PA bouts, while triglyceride responses are more closely related to greater duration and/or intensity. Blood pressure shows favourable acute responses across PA types, whereas higher PA intensity is associated with improved endothelial function. Tailoring strategies to interrupt SB with PA bouts may help inform approaches to improve cardiometabolic health.

Humans↗
PubMedDate not supplied

Influence of the endothelium on the responses to endogenous agonists in human internal mammary and gastroepiploic arteries.

The higher patency rate of internal mammary artery grafts compared to venous grafts has been ascribed to its endothelial function, namely a greater capacity to release endothelium-derived relaxing factor and to inhibit serotonin-induced contractions. Gastroepiploic and mammary arteries were obtained intraoperatively from 27 patients and suspended in organ chambers to record isometric tension. The relaxations to acetylcholine were similar in both vessels. The contractions to serotonin, normalized as a per cent of KCl (90 mM)-induced contractions, were 46 +/- 15% for the internal mammary artery and 18 +/- 5% for the gastroepiploic artery. Endothelium removal equally potentiated the responses to serotonin: the maximal responses (% of KCl) increased to 63 +/- 18% and 41 +/- 6%, respectively. The contractions to endothelin were also higher in the internal mammary artery: 166 +/- 19% vs 102 +/- 6% of KCl (p < 0.05), but were not affected by endothelium removal. However, the capacity to contract, expressed in tension developed, was higher in the gastroepiploic artery: the KCl (90 mM)-induced contraction was 2.6 +/- 0.3 g in the internal mammary vs 7.9 +/- 0.9 g in the gastroepiploic artery (p < 0.001). Histologically, similar wall thickness and paucity of atherosclerotic lesions were observed, but the medium was mainly elastic in the internal mammary and muscular in the gastroepiploic artery. Thus, despite a similar endothelial function and greater responsiveness of the mammary artery to endogenous vasoconstrictors when compared to a receptor-independent vasoconstrictor, the higher contractile capacity of the gastroepiploic artery might be a disadvantage in terms of graft function and patency.

Acetylcholine↗
PubMed1977

The endothelium: roles in thrombosis and hemostasis.

The renewed interest in endothelial function is based partly on success with tissue culture of endothelial cells. Endothelium functions primarily in the control of blood vessel wall permeability and in the provision of a blood-compatible lining surface. Recent findings indicate that endothelial cells are active metabolically in ways that may help prevent thrombosis. Endothelium actively degrades several different vasoactive compounds that circulate in blood and that can serve as platelet-aggregating agents. Endothelium also contains an inhibitor of platelet function and an activator of plasminogen, both of which can be released from the cell in response to appropriate stimuli. While intact endothelium functions primarily in prevention of thrombosis, damaged endothelium can contribute greatly to thrombus formation. Release of prostaglandins, adenine nucleotides, and other intracellular components from damaged endothelium can enhance platelet aggregation. Damaged endothelium may not function effectively in removal of vasoactive agents and may not release effective quantities of the inhibitor of platelet function or the activator of plasminogen. Altered endothelium exhibits tissue-factor activity, which can activate the extrinsic blood coagulation-system cascade. Finally, altered endothelial cells may contract and expose basement membrane to blood, thus enhancing thrombosis.

Blood Coagulation↗
PubMed1976

Human corneal endothelial layer repair during organ culture.

Circular freeze-thaw endothelial wounds were created on paired human corneas. Ultrastructural and physiological studies were performed after organ culture (OC) incubation at 37 C from 1 to 21 days as well as on fresh noncultured controls. As early as 24 hours after injury, OC corneas demonstrated ultrastructurally intact endothelial cells at the margin of the wound, elongating and sliding toward its center. All OC corneas were completely covered by ultrastructurally intact and physiologically functioning endothelial cells by seven days of OC. These cells were approximately twice normal size. Enlarged endothelial cells that maintained deturgescence function were seen in the wounded area after 14 and 21 days of OC. None of the fresh controls demonstrated deturgescence function and in none could ultrastructurally intact endothelial cells be found in the area of the wound. This confirms our hypothesis that during 37 C OC incubation, human corneal endothelium repairs defects in its layer by cells that are physiologically and ultrastructurally intact.

Cornea↗
PubMed2026

Premeal insulin administration lowers postprandial blood glucose and increases myocardial microvascular blood flow in people with type 1 diabetes: a randomised, crossover clinical trial.

AIMS/HYPOTHESIS: We aimed to evaluate whether prandial insulin timing affects vascular function in people with type 1 diabetes. Our hypothesis was that premeal insulin administration would lead to greater myocardial microvascular blood flow (MBF) via blunting postprandial hyperglycaemia. METHODS: People with type 1 diabetes between 18 and 35 years of age with BMI <30 kg/m2 underwent two protocols with a 1:1 randomised crossover design wherein prandial insulin was injected either 15 min before or 15 min after meal intake began. To provide a physiological comparison, age-, sex- and BMI-matched control participants completed one study where they consumed the same meal but received no exogenous insulin. Glucose, insulin, vascular function (including ultrasound measures of myocardial and skeletal muscle microvascular perfusion, aortic stiffness, brachial artery endothelial function) and biomarkers of systemic inflammation and endothelial dysfunction were assessed at baseline and then 2 h after meal ingestion within each protocol. The primary outcome was change in myocardial MBF within each protocol. Study personnel assessing outcomes were masked to group assignment. RESULTS: Eighteen people with type 1 diabetes and 18 matched control participants were analysed within each protocol. Glucose area under the curve was significantly greater (p=0.015) in the postmeal insulin study compared with the premeal insulin study in participants with type 1 diabetes. Myocardial microvascular flow velocity significantly increased (p=0.031) with premeal insulin administration in people with type 1 diabetes and this consequently led to greater myocardial MBF (p=0.044). There were no changes in myocardial MBF within the other protocols. Changes in vital signs were similar between all protocols. CONCLUSIONS/INTERPRETATION: Appropriately timed premeal insulin led to lower postprandial blood glucose along with increased myocardial MBF in people with type 1 diabetes. Further work is needed to determine the underlying aetiology of these changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04730882.

Humans↗
PubMed2026

Human iPSC-EV-loaded nanofiber stent coatings accelerate vascular repair by enhancing EGFR/HIF-1&#x3b1; signaling and suppressing ROCK1-mediated remodeling.

Arterial disease management is shifting from antiproliferative drug-eluting stents toward approaches that restore endothelial function and modulate smooth muscle cell (SMC) behavior. Stem cell-derived extracellular vesicles (EVs) carry miRNAs that promote endothelial proliferation and migration while restraining aberrant SMC growth and inflammation. Here, human induced pluripotent stem cell (iPSC)-derived EVs were collected by ultracentrifugation and incorporated into 50:50 poly (lactic-co-glycolic acid) (PLGA 503) core-shell nanofibrous membranes, which were fabricated as stent coatings for sustained release to overcome rapid clearance and poor tissue retention. EVs derived from three independent iPSC lines all enhanced tube formation in human umbilical vein endothelial cells (HUVECs) under hypoxic and serum-starved conditions and revealed a trend toward reduced platelet-derived growth factor-BB (PDGF-BB)-induced smooth muscle cell (SMC) migration. The fabricated core-shell nanofibers enabled sustained EV release, maintaining therapeutic efficacy for 28 days. Small RNA sequencing (NGS) analysis demonstrated that EVs from these independent iPSC lines shared miR-148a-3p and members of the miR-92 family, which collectively accounted for more than 75% of the reads within the 25 top-expressed miRNA set. In vitro, iPSC-EVs enhanced HUVEC proliferation and survival signaling by downregulating the negative regulators ERRFI1 and VHL, which are specific targets of miR-148a-3p and the miR-92 family, thereby activating the EGFR and HIF-1&#x3b1; axes and driving downstream ERK1/2 and VEGF expression under hypoxic and serum starvation stress conditions. Concurrently, iPSC-EVs prevented PDGF-BB-induced SMC phenotypic switching by downregulating ROCK1, a target of miR-148a-3p, thereby inhibiting downstream AKT and ERK signaling and preserving contractile markers while suppressing the synthetic phenotype. In vivo, the iPSC-EV-functionalized scaffolds significantly accelerated re-endothelialization and inhibited neointimal hyperplasia, evidenced by the upregulation of angiogenic factors (VEGF, CD31) and the concurrent suppression of pathological remodeling markers (&#x3b1;-SMA, MMPs) and inflammatory cytokines (IL-6, TGF-&#x3b2;1). Therefore, iPSC-EVs enriched with specific miRNAs and delivered via PLGA 503 core-shell nanofibers promote endothelial repair while suppressing SMC overgrowth, providing a promising strategy for vascular healing.

Core-shell nanofibers↗
PubMed1979

[Vascular endothelium (author's transl)].

Studies during recent years have shown the importance of the vascular endothelium in several physiological and pathological circumstances. The culture of endothelial cells has permitted the direct study of endothelial functions. The endothelium is a selective barrier between blood and tissues: the molecules cross it, according to their size, either through the intercellular junctions or through the cells by pinocytotic vesicles. The permeability is modulated by vasomotor agents and modified during endothelial regeneration, especially for the lipids. The endothelium plays a prominent part in the maintenance of the blood flow through its nonthrombogenic properties. It metabolizes circulating thrombogenic substances (arachidonic acid, adenosine diphosphate) and produces potent antiaggregating agents (prostacyclin and adenosine). It may also release a plasminogen activator promoting thrombolysis. The endothelial cells contribute to the formation of the basement membrane by synthesizing collagen and fibronectin, which are involved in platelet adhesion and aggregation to exposed subendothelium. On the other hand, the endothelium has a modulating influence on the local blood flow by producing vasoconstrictors (angiotensin II and III) and vasodilating agents (adenosine and prostacyclin). It is not necessary to elucidate the coordination of these functions and their relationship to the endothelial disorders in vascular diseases.

Actins↗
PubMed1992

[The value of ACE inhibitors in heart failure (mechanism of action)].

ACE-inhibitors improve symptoms and prognosis in patients with heart failure. The V-Heft II trial has demonstrated that the beneficial effect of these agents is superior to unspecific vasodilators. Besides sustained arterial and venous vasodilation the inhibition of the neurohumoral axis is thought to play an important role. Angiotensin II and catecholamines not only exert vasoconstrictor effects, but might also contribute to vascular and myocardial growth. Thus, it may not be surprising that the beneficial effects of ACE inhibitors in heart failure only emerge during long-term therapy rather than after short-term administration. It has been shown that these agents improve blood flow to skeletal muscle during exercise after chronic therapy (not acutely), and there is some preliminary evidence that improvement of endothelial function might be involved in this effect, i.e., by reducing the degradation of bradykinin, an endothelial vasodilator. ACE inhibitors reduce LV hypertrophy, an important risk factor for cardiovascular disease and prognosis. Moreover, there is experimental evidence that ACE inhibitors can prevent and even reverse interstitial fibrosis in the left ventricle. Although the plasma renin activity may be normal in patients with chronic heart failure, recent data using polymerase chain reaction indicate that the tissue cardiac renin angiotensin system is activated in the failing human heart as assessed by measurements of angiotensin converting enzyme mRNA and angiotensinogen mRNA which may be an important target for ACE-inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Clinical specular microscopy.

Clinical specular microscopy (CSM) has recently been introduced as a means of qualitative and quantitative examination of the human corneal endothelium at high magnification. With the aid of CSM, a decline in endothelial cell density with age has been documented and several endothelial abnormalities from disease or trauma can be detected. Donor material for corneal grafting can be examined by CSM and keratoplasty procedures can be designed to decrease endothelial damage. Cataract surgical procedures can cause endothelial cell loss. According to most studies, intracapsular extraction causes less cell loss than does phacoemulsification, and cataract extraction with intraocular lens (IOL) insertion causes the greatest loss. Cell loss from IOL can be minimized by decreasing lens-corneal contact. Elevated intraocular pressure may lead to endothelial cell loss, as may therapy with epinephrine. Endothelial toxicity of other drugs and solutions can be studied by CSM. While long term studies are necessary to correlate the morphologic changes detected by CSM with future endothelial function, shortterm studies can be helpful in developing medical and surgical techniques that minimize corneal endothelial trauma.

Adolescent↗
PubMed1975

Effect of epinephrine on the corneal edothelium.

Intracameral epinephrine has been advocated for treatment of iris bleeding and inadequate pupillary dilatation during intraocular surgery. Commercial epinephrine 1:1000 with its preservative sodium bisulfite damaged corneal endothelial function and ultrastructure in rabbit and monkey eyes with sodium bisulfite the source of the damage. Endothelial damage can be prevented with a 1:5000 dilution of commercially available epinephrine in 0.1% sodium bisulfite or freshly prepared epinephrine bitartrate 1:1000 with a bicarbonate Ringers.

Animals↗
PubMed1992

Zinc deficiency alters barrier function of cultured porcine endothelial cells.

Zinc is necessary for normal membrane function and stability. We postulated that Zn deficiency may disrupt the integrity of the vascular endothelium by decreasing its barrier function. To test this hypothesis, endothelial cells were cultured on polycarbonate filters and exposed to media enriched with either 1% fetal bovine serum (FBS) (low FBS; total Zn, 1.07 mumols/L medium) or 5% FBS (control; total Zn, 2.29 mumols/L) or low FBS plus two supplemental levels of Zn, 3.36 and 5.66 mumols total zinc/L. Endothelial cell barrier function, expressed as albumin transfer across cultured endothelial monolayers, was significantly lower in cultures exposed to low FBS compared with control medium. Supplementation with 5.66 mumols total Zn/L completely restored endothelial barrier function. A divalent cation chelator, 1,10-orthophenanthroline, was used to induce Zn deficiency in vitro. Compared with control cultures, the presence of 1,10-orthophenanthroline in the culture medium resulted in markedly lower endothelial barrier function that was increased by the addition of Zn but not calcium or magnesium. Activity of the membrane-bound zinc-dependent angiotensin-converting enzyme (ACE) was depressed by low zinc medium, whereas membrane-bound Ca(2+)-ATPase and total ATPase were not depressed. Furthermore, cells cultivated in low zinc medium did not have greater cytosolic release of adenine, indicating no increase in cell injury or death. These data suggest that Zn is vital to endothelial cell integrity and that Zn may play an important role in vascular endothelial barrier function.

Adenine↗
PubMed1992

Endothelial dysfunction of resistance arteries of spontaneously hypertensive rats.

Vascular relaxations are impaired in adult spontaneously hypertensive rats (SHRs) because of increased production of endothelium-derived, cyclooxygenase-dependent contractile factors. The objectives of the present study were to determine whether alterations in endothelial function precede the development of hypertension in SHRs and to characterize the contractile factor(s) produced by SHR endothelial cells. Mean systolic blood pressures were minimally (6 mm Hg) higher at 4 weeks of age in SHRs than in Wistar-Kyoto (WKY) rats. Endothelium-mediated relaxations of mesenteric and renal resistance arteries from SHRs and WKY rats were compared in myographs and arteriographs in paired experiments. Acetylcholine (ACh, 10(-9) to 10(-7) M) induced endothelium-dependent relaxations in precontracted mesenteric and renal resistance arteries that were similar in SHRs and WKY rats. At higher concentrations of ACh (10(-6) to 10(-5) M), relaxations were replaced by contractile responses in SHR but not in WKY rat resistance arteries. The contractile responses were endothelium dependent and were inhibited by indomethacin in both mesenteric and renal arteries. Thus, endothelial dysfunction precedes and may contribute to the development of accelerated hypertension in SHRs. SQ 29548, a prostaglandin H2 (PGH2)-thromboxane A2 receptor antagonist, blocked the contractile responses in renal but not in mesenteric resistance arteries. The contractile responses in mesenteric arteries were inhibited by 3-amino-1,2,4-triazole (10(-3) M), an inhibitor of superoxide production via the cyclooxygenase pathway. We conclude from these data that the endothelium-derived contracting factor (EDCF) produced in SHR renal arteries is most likely PGH2 whereas the contractile factor produced in mesenteric arteries is superoxide.

Acetylcholine↗
PubMed1976

Physiological function of regenerating endothelium.

A defined area, 4 mm. diameter, cryothermal injury was created on a rabbit cornea. Corneal thickness was measured at four distances from the limbus to the center of the cornea during the swelling phase after endothelial damage, and during the recovery period. Rapid initial swelling was followed by a period of stable maximum thickness over 24 hours. More swelling occurred centrally than peripherally. Eight days after injury the peripheral cornea regained normal thickness, and the central portion was normal thickness after 10 to 12 days. Histological examination of corneal endothelium showed that early migration of cells into the denuded area occurred 6 hours after injury. By 2 days, most of the denuded area was covered by endothelial cells, although the cells were large and irregular. The number of normal cells increased, and of irregular cells decreased, over the next five days, until two weeks after freezing all cells had a normal appearance. The recovery of physiologic endothelial function lags behind the histologic recovery by about four to five days, indicating that recovery of the normal endothelial permeability is possibly related to the status of the cellular junctions rather than covering of the posterior surface by cells per se.

Animals↗
PubMed1992

Endothelium-derived prostacyclin: effect of serum from women with normal and hypertensive pregnancy.

1. Pregnancy-induced hypertension (or pre-eclampsia) is characterized by vasoconstriction, platelet aggregation and altered capillary permeability, implying disordered endothelial function and/or structure. Serum from women with pregnancy-induced hypertension has been reported by others to be cytotoxic to endothelial cells in vitro. We hypothesized that such serum contains a factor that limits the ability of endothelial cells to produce and/or release prostacyclin. 2. Prostacyclin production by intact and damaged cultured human umbilical vein endothelial cells was measured after incubating these cells with serum from non-pregnant and normal pregnant women and women with pregnancy-induced hypertension. Confluent human umbilical vein endothelial cell monolayers (intact and damaged) were incubated with sera for 24 h at 37 degrees C followed by 1 h of incubation with added thrombin (stimulated production) or media (basal production). Supernatants were then collected for measurement of 6-keto-prostaglandin F1 alpha by radioimmunoassay. 3. Basal production of 6-keto-prostaglandin F1 alpha was greater in response to serum from non-pregnant women than to that from pregnant women. Within each group, sub-lethally damaged cells had a similar basal production of 6-keto-prostaglandin F1 alpha to that of intact cells. 4. Basal production of 6-keto-prostaglandin F1 alpha by intact or damaged cells incubated with sera from normal pregnant women and from women with pregnancy-induced hypertension was similar. 5. In all groups the addition of thrombin to intact endothelial cells increased 6-keto-prostaglandin F1 alpha production approximately 15-30-fold over basal levels, but only three- to five-fold in damaged endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1992

In vivo measurement of endothelium-dependent vasodilation with substance P in man.

Endothelial cells synthesize and metabolize vasoactive substances which are involved in the regulation of vascular tone. Among these factors, the endothelium-derived nitric oxide (NO) appears to be of major importance. Many studies observed an impairment of the generation, release, or the diffusion of endothelial NO across the vascular intima in laboratory animals with various experimental diseases such as hypercholesterolemia, atherosclerosis and hypertension. In human coronary arteries obtained from explanted hearts impaired endothelium-dependent relaxations were measured in atherosclerotic segments. The hypothesis of a decreased NO mediated vasodilation in patients with coronary artery disease was further underscored by in vivo studies in man using intracoronary infusions of the endothelium-dependent vasodilator acetylcholine and quantitative coronary angiographic measurements of the diameter changes. From these observations it was assumed that endothelial dysfunction, in particular a profound inability of the coronary endothelium to relax via NO dependent mechanisms may play an important role in the pathogenesis of abnormal coronary vasomotion. However, further investigations in man reveal that the ability of the coronary endothelium of patients with coronary artery disease or vasospastic angina to produce endothelial NO is less affected as judged from the effects of acetylcholine. In recent investigations a largely preserved endothelial function could be measured in these patients when the endothelium-dependent vasodilator substance P was used as a tool for the measurement of NO dependent relaxation. Thus, endothelial dysfunction does not appear to serve as a major cause of abnormal vasoconstriction in coronary artery disease or vasospastic angina in man.

Acetylcholine↗
PubMed2026

Extracellular vesicle miR-93-5p cargo regulates glomerular endothelial cell damage in Alport syndrome.

Modulation of miRNA expression in glomerular cells is associated with renal disease. Here, we investigated the role of miR-93-5p in mitigating glomerular damage in Alport syndrome and whether the disease-modifying activity of extracellular vesicles from human amniotic fluid stem cells (hAFSC-EVs) is mediated by their miR-93-5p cargo. We identified downregulation of miR-93-5p specifically in glomerular endothelial cells in Alport syndrome along disease progression. Silencing of miR-93-5p in hAFSC-EVs changed the transcriptomic and proteomic profile, regulating EV disease-modifying activity. Compared with naive hAFSC-EVs, silenced hAFSC-EVs did not rescue glomerular endothelial function in vitro and did not restore kidney function in vivo. We established that hAFSC-EVs regulate VEGFR1 and VEGFR2 signaling by miR-93-5p cargo transfer, highlighting that miR-93-5p can restore glomerular endothelial cell biology. Spatial transcriptomics analysis of hAFSC-EV-injected kidneys showed that these EVs can reverse pathways altered during disease progression by stimulating proregenerative processes, specifically in the glomerulus, by regulating miR-93-5p targets. Alteration of glomerular endothelial cell transcriptomics and miR-93-5p targets was also confirmed in biopsies of patients with Alport syndrome using spatial molecular imaging. We demonstrated the critical role of miR-93-5p in glomerular endothelial cells and the capability of hAFSC-EVs to regulate miR-93-5p and its targets in Alport syndrome.

Humans↗