Capillary Recruitment Research Articles

Mast cells and arteriogenesis: A systematic review.

Vascular occlusive diseases remain a major health burden worldwide, necessitating a deeper understanding of the adaptive responses that mitigate their impact. Arteriogenesis, the growth and remodeling of collateral vessels in response to arterial occlusion, is a vital defense mechanism that counteracts fluid shear stress-induced vascular stenosis or occlusion. While physical factors driving arteriogenesis have been extensively studied, the specific cellular mediators involved are poorly understood. Notably, the role of innate and adaptive immune cells, particularly mast cells, in arteriogenesis has received limited attention. This systematic review bridges this knowledge gap by investigating the contribution of mast cells to vascular cell proliferation and leukocyte recruitment in arteriogenesis. A comprehensive search of major databases using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines reveals the critical connection between mast cells, inflammatory cells, innate immune cells, and growth factors in arteriogenesis. Our findings highlight the molecular mechanisms of mast cell activation, sheer stress exertion, and pro-arteriogenic growth factor recruitment. Furthermore, we explore the endogenous and exogenous factors, including nitrite, dipyridamole, thrombin, and cobra venom, triggering mast cell-mediated release of pro-arteriogenic factors. Additionally, we examine the impact of recombinant parathyroid hormone (rPTH) therapy on mast cell numbers and arteriogenesis in bone defect and allograft healing. Our review provides compelling evidence for the pro-arteriogenic role of mast cells, particularly during the early inflammatory phase of vessel occlusion, suggesting that targeting mast cell activation may be a promising therapeutic strategy for enhancing arteriogenesis and treating ischemia-related diseases.

The role of biological soil crusts in vascular plant recruitment in the Loess Plateau region, China

The role of biological soil crusts in vascular plant recruitment in the Loess Plateau region, China

BLUNTED SKELETAL MUSCLE MICROVASCULAR BLOOD FLOW IS A POTENTIAL UNDERLYING MECHANISM FOR EXERCISE INTOLERANCE IN ADULTS WITH ATRIAL FIBRILLATION

INTRODUCTION & AIMS Approximately 45% of adults living with atrial fibrillation (AF) experience exercise intolerance (EI). However, the mechanisms of EI in AF are not well understood. We aimed to determine whether impaired skeletal muscle microvascular blood flow (MBF), not macrovascular, responses to peak exercise is a plausible explanation for EI in adults with AF. METHODS Adults with AF and healthy controls completed a Modified Bruce treadmill protocol to obtain peak oxygen uptake (V̇O2peak). Skeletal muscle microvascular blood volume, velocity, and flow in the vastus lateralis muscle was assessed using contrast enhanced ultrasound. Superficial femoral artery diameter, blood velocity and flow were assessed using 2D and Doppler ultrasound. Vascular measurements were collected at rest, immediately post-exercise, and 30 minutes post-exercise. RESULTS Nine adults with AF (age: 62±5 years, 66% females, BMI: 29.7±4.2 kg/m2, V̇O2peak: 24.3±6.1 mL/kg/min) and seven controls (age: 63±10 years, 57% females, BMI: 26.7±1.7 kg/m2, V̇O2peak: 31.0±7.5 mL/kg/min) participated. One participant was in AF during testing. A significant group x time interaction in skeletal muscle MBF (p=0.04) and near significant interaction in blood volume (capillary recruitment, p=0.08) was observed. Post-hoc analysis revealed adults with AF had a significantly blunted MBF at 30 minutes post-exercise (-1.3 fold versus control, p=0.01) and reduced microvascular blood volume (i.e. capillary recruitment) pre- and 30 minutes post-exercise (-6.6 fold [p=0.01] and -9.4 fold [p=0.01] versus controls). No differences were observed for changes in skeletal muscle microvascular blood velocity, or femoral artery diameter, blood velocity or flow. CONCLUSION Despite similar femoral artery blood flow responses, adults with AF have lower skeletal muscle MBF responses to peak exercise which may be driven by a reduced capillary recruitment in the skeletal muscle. Our findings provide new insight into vascular complications which may partially explain EI in those with AF.

Insulin-Mediated Capillary Recruitment Is Absent in the Cutaneous Microvasculature of Women with a History of Gestational Diabetes Mellitus

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater risk of developing cardiovascular disease and type II diabetes compared to women who had an uncomplicated pregnancy (HC). Although the mechanisms underlying this increased risk are unclear, emerging evidence suggests that microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation, persists after pregnancy complicated by GDM. Whether this microvascular dysfunction reduces insulin-mediated responses in these women is unexplored. We hypothesized that insulin-mediated capillary recruitment would be attenuated in women with a history of GDM via NO-dependent mechanisms. 24 women (n=12/group; HC: 35±1 years, 24±4 months post-partum; GDM: 33±1 years, 21±3 months postpartum) underwent intradermal microdialysis, which involved the placement of 2 fibers in the ventral forearm for the local delivery of 10−4M insulin alone or 10−4M insulin+15mM NG-nitro-L-arginine methyl ester (L-NAME, NO-synthase inhibitor). The cutaneous blood flow response to post-occlusive reactive hyperemia (PORH; 5 minutes) was assessed before and during insulin perfusion. Red blood cell flux was measured continuously over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=flux/mean arterial pressure), normalized to maximum (%CVCmax), and presented as PORH area under the curve (AUC, %CVCmax• sec−1). Microvascular capillary recruitment was assessed as ΔAUC (pre-insulin AUC - insulin AUC). Insulin perfusion increased PORH in HC (pre-insulin: 4066±490 vs. insulin: 7848±978 AUC; p=0.03) but had no effect in GDM (pre-insulin: 3765±293 vs. insulin: 6196±779 AUC; p=0.26). Insulin perfusion did not increase PORH at the L-NAME site in either group (p>0.05). Within groups, L-NAME perfusion reduced insulin-mediated capillary recruitment in HC (control: 3781±1109 vs. L-NAME: 470±945 ΔAUC; p=0.04) but not GDM (control: 2431±796 vs. L-NAME: -41±1014 ΔAUC, p=0.11). These data suggest that insulin-mediated capillary recruitment assessed by PORH in the cutaneous circulation is mediated by NO-dependent mechanisms in healthy women with a history of uncomplicated pregnancy and attenuated in healthy women with a history of GDM. This reduction in insulin-mediated microvascular responses may contribute to the increased risk of cardiovascular disease and type II diabetes in these women. UI Fraternal Order of Eagles Diabetes Research Center Catalyst Grant; NIH HL169201. This is the full abstract presented at the American Physiology Summit 2024 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.

Microcirculation, endothelium and glycocalyx changes associated with the use of milrinone in children with septic shock.

The goal of fluid resuscitation and the use of inotropes in septic shock has traditionally focused on improving blood pressure and cardiac output, without considering the microcirculatory changes. Reaching macrocirculatory goals but with persistent microcirculatory abnormalities (hemodynamic incoherence) in septic shock has been associated with greater organ dysfunction and mortality. The objective of this study was to evaluate the microcirculation (flow and capillary density) and endothelial glycocalyx changes associated with the use of milrinone in children with septic shock, as well as their relationship with clinical variables and organ dysfunction. A prospective cohort study from February 2022 to January 2023 at a university hospital (Fundación Cardioinfantil-Instituto de Cardiología). Sublingual video microscopy was used to evaluate capillary density, microvascular flow rates and perfused boundary region (PBR-inverse parameter of glycocalyx thickness-abnormal if >2.0 microns). The primary outcome was the association between microcirculation and endothelial glycocalyx changes related to the use of milrinone. A total of 140 children with a median age of two years [interquartile range (IQR) 0.58-12.1] were included. About 57.9% (81/140) of the patients received milrinone infusions. Twenty-four hours after receiving milrinone, the patients maintained functional capillary density (P<0.01) and capillary recruitment capacity (P=0.04) with no changes in capillary blood volume versus those who did not receive milrinone. Children under two years old who received milrinone had better 4-6-micron capillary density than older children [odds ratio (OR) 0.33; 95% confidence interval (95% CI): 0.12-0.89; P=0.02] and less endothelial glycocalyx degradation [adjusted OR (aOR) 0.34 95% CI: 0.11-0.99; P=0.04]. These changes persisted despite elevated ferritin (aOR 0.41; 95% CI: 0.18-0.93; P=0.03). Prolonged capillary refill and elevated lactate were correlated with microcirculation changes in both groups. The patients who died had the highest PBR levels (P=0.04). Children with septic shock who receive milrinone infusions have microcirculation changes compared with those who do not receive them. The group that received milrinone was found to maintain functional capillary density and capillary recruitment capacity and have less endothelial glycocalyx degradation 24 hours after administration. These changes were present despite the inflammatory response and were more significant in those under two years of age.

Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice.

Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of post-operative liver failure, known as the small for size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in a SFSS liver remnant initiated early angiogenesis, improving vascular architecture, safeguarding against liver failure and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS, its impact on hepatocyte function and subsequent liver failure. Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered post-hepatectomy survival rates. Early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells (EPC), increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony stimulating factor (G-CSF) in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and EPC recruitment, but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of AAV8-TBG-HNF4α virus for hepatocyte-specific overexpression of HNF4α, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of HNF4α overexpression and G-CSF treatment rescued survival after SFSS-setting hepatectomy. In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS-hepatectomy, it is essential to adopt a two-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.

Peripheral microvascular function is linked to cardiac involvement on cardiovascular magnetic resonance in systemic sclerosis-related pulmonary arterial hypertension.

Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation, and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, patients with SSc-PAH demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relationship between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy (NCM) in patients with SSc-PAH is evaluated and compared with patients with idiopathic PAH (IPAH). Patients with SSc-PAH and IPAH underwent CMR, echocardiography, and NCM with post-occlusive reactivity hyperaemia (PORH) testing on the same day. CMR imaging included T2 (oedema), native, and post-contrast T1 mapping to measure the extracellular volume fraction (ECV, fibrosis) and adenosine-stress-perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis, and myocardial perfusion. SSc-PAH patients (n = 20) had higher T2 values and a trend towards a higher ECV, compared with IPAH patients (n = 5), and a lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV and T2 (r = -0.443 and -0.464, respectively, P < 0.05 for both) and with markers of diastolic dysfunction on echocardiography. PORH testing, but not NCD, correlated with the relative myocardial upslope (r = 0.421, P < 0.05). SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared with IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

HIF-1A INITIATES VASCULAR RECRUITMENT AND IRREVERSIBLE FIBROSIS IN TENDON

Tendinopathy is the most common form of chronic tendon disorders, accounting for up 30% of all musculoskeletal clinic visits [1]. In tendon disease, the largely avascular tendon tissue often becomes hypervascularized and fibrotic [2]. As blood vessel growth and angiogenic signaling molecules are often induced by the lack of adequate nutrients and oxygen, hypoxic signaling is speculated to be a root cause of tendon neovascularization and tendinopathy [3,4,5]. However, how the vascular switch is initiated in tendons, and how vascularization contributes to tendon pathology remains unknown. In this talk, we provide evidence that HIF-1α is implicated in tendon disease and HIF-1α stabilization in human tendon cells induces vascular recruitment of endothelial cells via VEGFa secretion. More interesting, HIF-1α stabilization in tendon cells in vivo, seems to recapitulate all main features of fibrotic human tendon disease, including vascular ingrowth, matrix disorganization, changes in tissue mechanics, cell proliferation and innervation. Surprisingly, in vivo knock-out of VEGFa rescued angiogenesis in the tendon core but it did not affect tendon mechanical properties and tissue pathophysiological changes, suggesting that blood vessels ingrowth might not be a primary cause but a consequence of HIF-1α activation.

Impaired Capillary Recruitment Capacity in Obesity: A Subgroup Analysis of Prospective Observational Study on Anesthesia Effects.

BACKGROUND This subgroup analysis of prospective observational research, involving 71 participants, compared the effects of anesthesia on microvascular reactivity in obese vs lean individuals using near-infrared spectroscopy and vascular occlusion tests. The correlation between the body mass index (BMI) and microvascular reactivity under general anesthesia was also investigated. MATERIAL AND METHODS This study enrolled adult patients classified as American Society of Anesthesiologists physical status I or II, undergoing elective surgery under general anesthesia. The microcirculatory variables measured before (Tpre) and 30 min following the induction of anesthesia (Tpost) were as follows: baseline tissue oxygen saturation (StO₂), occlusion slope (∇occl), and recovery slope (∇recov). The patients were grouped according to their BMI (lean [BMI <25 kg/m²] vs obese [BMI ≥25 kg/m²]). Data are presented as medians and interquartile ranges. RESULTS There were 43 patients in the lean group and 28 in the obese group. At Tpre, baseline StO2, ∇occl, and ∇recov were not different between the 2 groups (P=0.860, 0.659, and 0.518, respectively). At Tpost, the baseline StO₂ and ∇occl were not different between the 2 groups (P=0.343 and 0.791); however, the ∇recov was lower in the obese group than in the lean group (3.245 [2.737, 3.977] vs 4.131 [3.491, 4.843], P=0.003). At Tpost, BMI showed a moderate correlation with ∇recov (correlation coefficient: -0.319, P=0.007). CONCLUSIONS In obese patients, capillary recruitment capacity during general anesthesia is compromised compared to lean patients.

Vascular co-option in resistance to anti-angiogenic therapy.

Three different mechanisms of neovascularization have been described in tumor growth, including sprouting angiogenesis, intussusceptive microvascular growth and glomeruloid vascular proliferation. Tumors can also grow by means of alternative mechanisms including vascular co-option, vasculogenic mimicry, angiotropism, and recruitment of endothelial precursor cells. Vascular co-option occurs in tumors independently of sprouting angiogenesis and the non-angiogenic cancer cells are described as exploiting pre-existing vessels. Vascular co-option is more frequently observed in tumors of densely vascularized organs, including the brain, lung and liver, and vascular co-option represents one of the main mechanisms involved in metastasis, as occurs in liver and lung, and resistance to anti-angiogenic therapy. The aim of this review article is to analyze the role of vascular co-option as mechanism through which tumors develop resistance to anti-angiogenic conventional therapeutic approaches and how blocking co-option can suppress tumor growth.

Osteoprogenitor recruitment and differentiation during intracortical bone remodeling of adolescent humans.

Recruitment and proliferation of osteoprogenitors during the reversal-resorption phase, and their differentiation into mature bone-forming osteoblasts is crucial for initiation of bone formation during bone remodeling. This study investigates the osteoprogenitors' gradual recruitment, proliferation, and differentiation into bone-forming osteoblasts within intracortical remodeling events of healthy adolescent humans. The study was conducted on cortical bone specimens from 11 adolescent human controls - patients undergoing surgery due to coxa valga. The osteoprogenitor recruitment route and differentiation into osteoblasts were backtracked using immunostainings and in situ hybridizations with osteoblastic markers (CD271/NGFR, osterix/SP7, COL3A1 and COL1A1). The osteoblastic cell populations were defined based on the pore surfaces, and their proliferation index (Ki67), density and number/circumference were estimated in multiplex-immunofluorescence (Ki67, TRAcP, CD34) stained sections. During the reversal-resorption phase, osteoclasts are intermixed with (COL3A1+NFGR+) osteoblastic reversal cells, which are considered to be osteoprogenitors of (COL1A1+SP7+) bone-forming osteoblasts. Initiation of bone formation requires a critical density of these osteoprogenitors (43±9 cells/mm), which is reached though proliferation (4.4±0.5% proliferative) and even more so through recruitment of osteoprogenitors, but challenged by the ongoing expansion of the canal circumference. These osteoprogenitors most likely originate from osteoblastic bone lining cells and mainly lumen osteoprogenitors, which expand their population though proliferation (4.6±0.3%) and vascular recruitment. These lumen osteoprogenitors resemble canopy cells above trabecular remodeling sites, and like canopy cells they extend above bone-forming osteoblasts where they may rejuvenate the osteoblast population during bone formation. Initiation of bone formation during intracortical remodeling requires a critical density of osteoprogenitors on eroded surfaces, which is reached though proliferation and recruitment of local osteoprogenitors: bone lining cells and lumen osteoprogenitors.

Treatment of microvascular angina with the coronary sinus reducer: a first experience

Abstract The Coronary Sinus Reducer (CSR) is an hourglass-shaped device approved for the treatment of refractory angina. Its percutaneous implantation in the coronary sinus leads to a retrograde increase in venous pressure, which is thought to improve capillary recruitment and perfusion to the ischemic myocardium. No data is however available on the use of the CSR to treat microvascular angina, an increasingly recognized but still poorly understood condition. In this preliminary study, we evaluated the efficacy of the CSR in a small cohort of patients with non-obstructive disease. We screened consecutive patients from the prospective COMPLEX registry that received a CSR for refractory angina between June 2018 and November 2022. Inclusion criteria were the absence of obstructive coronary artery disease (&amp;lt;50% narrowing in all coronary arteries, or a negative intracoronary fractional flow reserve test) and no prior history of revascularization. Endpoints were angina and dyspnea symptoms, evaluated with the Canadian Cardiovascular Society (CCS) and the New York Hearth Association (NYHA) scores respectively, procedural success rate, and major adverse cardiovascular events (MACE), defined as a composite of all-cause mortality, cardiovascular death, acute coronary syndromes (ACS) and heart failure (HF) hospitalizations. We ultimately enrolled 8 patients; 6 (75%) were females and mean age was 67.8±9.9 years. Their baseline characteristics are further depicted in table 1. Microvascular dysfunction was invasively confirmed in 5 (62.5%) patients; mean index of microvascular resistance (IMR) was 32.8±15.7 and mean coronary flow reserve (CFR) was 1.7±0.7. In one patient, reduced global CFR (1.4) was evident on cardiac magnetic resonance examination. At baseline, mean CCS class was 2.9±0.6, NYHA class 2±0.9, and number of antianginal drugs 2.6±1.6. Procedural success was 100%, with only one patient experiencing a procedure-related complication (sternocleidomastoid muscle hematoma requiring no intervention). At a median follow-up of 647.5 days (IQR 132-732), mean CCS class was 1.5±0.8, NYHA class 1.9±0.9 and number of antianginal drugs 1.9±1.1. All patients improved by ≥1 CCS class and 3 (37.5%) by ≥2 CCS classes. No MACE was observed. To the best of our knowledge, we present the first report of CSR implantation for the treatment of microvascular angina. Our positive results are particularly promising given the paucity of treatment options currently available for the condition, but larger studies are needed to confirm these findings.table 1figure 1

The effect of heat on lung diffusing capacity for carbon monoxide (DLCO) during cycling exercise.

This study aimed to quantify the combined effects of heat exposure and exercise of increasing intensity on pulmonary blood flow using lung diffusing capacity for carbon monoxide (DLCO) as an indirect measure. We hypothesized that, during exercise in the heat, the well-documented increase in skin blood flow for thermoregulation would lead to alterations in pulmonary blood flow and a subsequent fall in DLCO versus a thermoneutral condition. Nine healthy subjects (4 F/5M, 20-45years, VO2max 46.7 ± 5.8mL/kg/min) completed three 15-min stages including rest and during cycling at 20 and 40% of maximum workload (Wmax) in either thermoneutral (TN; 22.2 ± 0.6°C) or heat (HT; 39.4 ± 0.4°C) conditions. DLCO, minute ventilation (VE), oxygen consumption ([Formula: see text]), heart rate (HR), and core (TC) and skin temperature (Tsk) were measured. DLCO showed a significant interaction between exercise intensity and heat (P = 0.019); post hoc testing revealed that DLCO was higher at 40% of Wmax in HT vs. TN (53.2 ± 10.6 vs 50.0 ± 10.3mL/min/mmHg, P = 0.003) only. VE and [Formula: see text] showed no difference in HT vs. TN. HR was higher in HT vs. TN (P < 0.001). TC and Tsk showed a significant interaction between temperature and intensity (P < 0.05). The unexpected increase in DLCO during exercise in HT vs. TN conditions suggests a larger lung surface area for gas exchange, perhaps due to increased pulmonary capillary recruitment and/or distension secondary to a higher cardiac output (Q) in the heat. This study furthers our understanding of how heat exposure might impact pulmonary blood flow, specifically as assessed via DLCO.

Microcirculatory Monitoring in Children with Congenital Heart Disease Before and After Cardiac Surgery

In this prospective observational study, we investigated whether congenital heart disease (CHD) affects the microcirculation and whether the microcirculation is altered following cardiac surgery with cardiopulmonary bypass (CPB). Thirty-eight children with CHD undergoing cardiac surgery with CPB and 35 children undergoing elective, non-cardiac surgery were included. Repeated non-invasive sublingual microcirculatory measurements were performed with handheld vital microscopy. Before surgery, children with CHD showed similar perfused vessel densities and red blood cell velocities (RBCv) but less perfused vessels (p < 0.001), lower perfusion quality (p < 0.001), and higher small vessel densities (p = 0.039) than children without CHD. After cardiac surgery, perfused vessel densities and perfusion quality of small vessels declined (p = 0.025 and p = 0.032), while RBCv increased (p = 0.032). We demonstrated that CHD was associated with decreased microcirculatory perfusion and increased capillary recruitment. The microcirculation was further impaired after cardiac surgery. Decreased microcirculatory perfusion could be a warning sign for altered tissue oxygenation and requires further exploration.Graphical abstract

Activation of ryanodine-sensitive calcium store drives pseudo-allergic dermatitis via Mas-related G protein-coupled receptor X2 in mast cells.

Mast cell (MC) activation is implicated in the pathogenesis of multiple immunodysregulatory skin disorders. Activation of an IgE-independent pseudo-allergic route has been recently found to be mainly mediated via Mas-Related G protein-coupled receptor X2 (MRGPRX2). Ryanodine receptor (RYR) regulates intracellular calcium liberation. Calcium mobilization is critical in the regulation of MC functional programs. However, the role of RYR in MRGPRX2-mediated pseudo-allergic skin reaction has not been fully addressed. To study the role of RYR in vivo, we established a murine skin pseudo-allergic reaction model. RYR inhibitor attenuated MRGPRX2 ligand substance P (SP)-induced vascular permeability and neutrophil recruitment. Then, we confirmed the role of RYR in an MC line (LAD2 cells) and primary human skin-derived MCs. In LAD2 cells, RYR inhibitor pretreatment dampened MC degranulation (detected by β-hexosaminidase retlease), calcium mobilization, IL-13, TNF-α, CCL-1, CCL-2 mRNA, and protein expression activated by MRGPRX2 ligands, namely, compound 48/80 (c48/80) and SP. Moreover, the inhibition effect of c48/80 by RYR inhibitor was verified in skin MCs. After the confirmation of RYR2 and RYR3 expression, the isoforms were silenced by siRNA-mediated knockdown. MRGPRX2-induced LAD2 cell exocytosis and cytokine generation were substantially inhibited by RYR3 knockdown, while RYR2 had less contribution. Collectively, our finding suggests that RYR activation contributes to MRGPRX2-triggered pseudo-allergic dermatitis, and provides a potential approach for MRGPRX2-mediated disorders.

Histopathologic Validation of Stress T1 Mapping in Myocardial Ischemia: Another Step toward Clinical Translation?

Histopathologic Validation of Stress T1 Mapping in Myocardial Ischemia: Another Step toward Clinical Translation?

Pulmonary Capillary Recruitment Is Attenuated Post Left Ventricular Assist Device Implantation

There is limited knowledge of pulmonary physiology and pulmonary function after continuous flow-left ventricular assist device (CF-LVAD) implantation. Therefore, this study investigated whether CF-LVAD influenced pulmonary circulation by assessing pulmonary capillary blood volume and alveolar-capillary conductance in addition to pulmonary function in patients with heart failure. Seventeen patients with severe heart failure who were scheduled for CF-LVAD implantation (HeartMate II, III, Abbott, Abbott Park, IL or Heart Ware, Medtronic, Minneapolis, MN) participated in the study. They underwent pulmonary function testing (measures of lung volumes and flow rates) and unique measures of pulmonary physiology using a rebreathe technique that quantified the diffusing capacity of the lungs for carbon monoxide (DLCO) and diffusing capacity of the lungs for nitric oxide before and 3months after CF-LVAD implantation. After CF-LVAD, pulmonary function was not significantly changed (p >0.05). For lung diffusing capacity, alveolar volume (VA) was not changed (p=0.47), but DLCO was significantly reduced (p=0.04). After correcting for VA, DLCO/VA showed a trend toward reduction (p=0.08). For the alveolar-capillary component, capillary blood volume (Vc) was significantly reduced (p=0.04), and alveolar-capillary membrane conductance trended toward a reduction (p=0.06). However, alveolar-capillary membrane conductance/Vc was not altered (p=0.92). In conclusion, soon after CF-LVAD implantation, Vc is reduced likely because of pulmonary capillary derecruitment, which contributes to the decrease in lung diffusing capacity.

Peripheral perfusion index in critically ill COVID-19 and its association with multiorgan dysfunction

Introduction: Severe cases of COVID-19 presented a high incidence of multi-organ dysfunction syndrome (MODS) during their evolution. This was attributed to a theoretical cytokine storm, where microcirculatory disorders would play a fundamental role, causing these patients to present a sepsis-like pattern as observed in sublingual microcirculation studies. The evidence in this regard is controversial. The Peripheral Perfusion Index is a reliable method to continuously and non-invasively assess the microcirculatory bed, which assesses the pulsatile (PPI) component of the plethysmographic pulse curve. Methods: We conducted a prospective observational study to evaluate the behavior of the PPI in patients with severe respiratory failure due to SARS-CoV-2 and its association with SDOM. Results: We evaluated 60 patients with APACHE II 14.6 ± 4.4 and SOFA 4.7 ± 2.1. 55% of the patients presented SDOM. Perfusion monitoring showed IP values of 5.32 ± 1.87 that were associated with normal lactate levels of 1.49 mmol/L (min 0.89/ max 2.20 mmol/L). The PPI values between the living and the dead did not show a significant difference (p = 0.854) or the presence of SDOM. The PPI values between the patients who presented renal failure, hemodynamics, or perfusion disorders were determined by the presence of hyperlactatemia, and for those who did not present these characteristics, no statistical difference was found; neither when stratified by PaFiO2 ratio. Mortality was 55%. Conclusion: In our series of patients with severe pneumonia due to COVID-19, we found high PPI values, which would correspond to a pattern of capillary recruitment, and the associated organ injury could not be substantiated by this phenomenon.

GPR35 and mediators from platelets and mast cells in neutrophil migration and inflammation.

Neutrophil recruitment from circulation to sites of inflammation is guided by multiple chemoattractant cues emanating from tissue cells, immune cells, and platelets. Here, we focus on the function of one G-protein coupled receptor, GPR35, in neutrophil recruitment. GPR35 has been challenging to study due the description of multiple ligands and G-protein couplings. Recently, we found that GPR35-expressing hematopoietic cells respond to the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). We discuss distinct response profiles of GPR35 to 5-HIAA compared to other ligands. To place the functions of 5-HIAA in context, we summarize the actions of serotonin in vascular biology and leukocyte recruitment. Important sources of serotonin and 5-HIAA are platelets and mast cells. We discuss the dynamics of cell migration into inflamed tissues and how multiple platelet and mast cell-derived mediators, including 5-HIAA, cooperate to promote neutrophil recruitment. Additional actions of GPR35 in tissue physiology are reviewed. Finally, we discuss how clinically approved drugs that modulate serotonin uptake and metabolism may influence 5-HIAA-GPR35 function, and we speculate about broader influences of the GPR35 ligand-receptor system in immunity and disease.

PDGF-BB signaling via PDGFR-β regulates the maturation of blood vessels generated upon vasculogenic differentiation of dental pulp stem cells.

A functional vascular network requires that blood vessels are invested by mural cells. We have shown that dental pulp stem cells (DPSC) can undergo vasculogenic differentiation, and that the resulting vessels anastomize with the host vasculature and become functional (blood carrying) vessels. However, the mechanisms underlying the maturation of DPSC-derived blood vessels remains unclear. Here, we performed a series of studies to understand the process of mural cell investment of blood vessels generated upon vasculogenic differentiation of dental pulp stem cells. Primary human DPSC were co-cultured with primary human umbilical artery smooth muscle cells (HUASMC) in 3D gels in presence of vasculogenic differentiation medium. We observed DPSC capillary sprout formation and SMC recruitment, alignment and remodeling that resulted in complex vascular networks. While HUASMC enhanced the number of capillary sprouts and stabilized the capillary network when co-cultured with DPSC, HUASMC by themselves were unable to form capillary sprouts. In vivo, GFP transduced human DPSC seeded in biodegradable scaffolds and transplanted into immunodeficient mice generated functional human blood vessels invested with murine smooth muscle actin (SMA)-positive, GFP-negative cells. Inhibition of PDGFR-β signaling prevented the SMC investment of DPSC-derived capillary sprouts in vitro and of DPSC-derived blood vessels in vivo. In contrast, inhibition of Tie-2 signaling did not have a significant effect on the SMC recruitment in DPSC-derived vascular structures. Collectively, these results demonstrate that PDGF-BB signaling via PDGFR-β regulates the process of maturation (mural investment) of blood vessels generated upon vasculogenic differentiation of human dental pulp stem cells.