Connexin37 Regulates Cell Cycle in the Vasculature.

Control of vascular cell growth responses is critical for development and maintenance of a healthy vasculature. Connexins - the proteins comprising gap junction channels - are key regulators of cell growth in diseases such as cancer, but their involvement in controlling cell growth in the vasculature is less well appreciated. Connexin37 (Cx37) is one of four connexin isotypes expressed in the vessel wall. Its primary role in blood vessels relies on its unique ability to transduce flow-sensitive signals into changes in cell cycle status of endothelial (and perhaps, mural) cells. Here, we review available evidence for Cx37's role in the regulation of vascular growth, vessel organization, and vascular tone in healthy and diseased vasculature. We propose a novel mechanism whereby Cx37 accomplishes this with a phosphorylation-dependent transition between closed (growth-suppressive) and multiple open (growth-permissive) channel conformations that result from interactions of the C-terminus with cell-cycle regulators to limit or support cell cycle progression. Lastly, we discuss Cx37 and its downstream signaling as a novel potential target in the treatment of cardiovascular disease, and we address outstanding research questions that still challenge the development of such therapies.

Anatomy and function of the lymphatic vessels in the parietal pleura and their plasticity under inflammation in mice.

Inflammatory pleuritis often causes pleural effusions, which are drained through lymphatic vessels (lymphatics) in the parietal pleura. The distribution of button- and zipper-like endothelial junctions can identify the subtypes of lymphatics, the initial, pre-collecting, and collecting lymphatics. Vascular endothelial growth factor receptor (VEGFR)-3 and its ligands VEGF-C/D are crucial lymphangiogenic factors. Currently, in the pleura covering the chest walls, the anatomy of the lymphatics and connecting networks of blood vessels are incompletely understood. Moreover, their pathological and functional plasticity under inflammation and the effects of VEGFR inhibition are unclear. This study aimed to learn the above-unanswered questions and immunostained mouse chest walls as whole-mount specimens. Confocal microscopic images and their 3-dimensional reconstruction analyzed the vasculatures. Repeated intra-pleural cavity lipopolysaccharide challenge induced pleuritis, which was also treated with VEGFR inhibition. Levels of vascular-related factors were evaluated by quantitative real-time polymerase chain reaction. We observed the initial lymphatics in the intercostals, collecting lymphatics under the ribs, and pre-collecting lymphatics connecting both. Arteries branched into capillaries and gathered into veins from the cranial to the caudal side. Lymphatics and blood vessels were in different layers with an adjacent distribution of the lymphatic layer to the pleural cavity. Inflammatory pleuritis elevated expression levels of VEGF-C/D and angiopoietin-2, induced lymphangiogenesis and blood vessel remodeling, and disorganized the lymphatic structures and subtypes. The disorganized lymphatics showed large sheet-like structures with many branches and holes inside. Such lymphatics were abundant in zipper-like endothelial junctions with some button-like junctions. The blood vessels were tortuous and had various diameters and complex networks. Stratified layers of lymphatics and blood vessels were disorganized, with impaired drainage function. VEGFR inhibition partially maintained their structures and drainage function. These findings demonstrate anatomy and pathological changes of the vasculatures in the parietal pleura and their potential as a novel therapeutic target.

Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling.

The extracellular matrix (ECM) initiates mechanical cues that activate intracellular signaling through matrix-cell interactions. In blood vessels, additional mechanical cues derived from the pulsatile blood flow and pressure play a pivotal role in homeostasis and disease development. Currently, the nature of the cues from the ECM and their interaction with the mechanical microenvironment in large blood vessels to maintain the integrity of the vessel wall are not fully understood. Here, we identified the matricellular protein thrombospondin-1 (Thbs1) as an extracellular mediator of matrix mechanotransduction that acts via integrin αvß1 to establish focal adhesions and promotes nuclear shuttling of Yes-associated protein (YAP) in response to high strain of cyclic stretch. Thbs1-mediated YAP activation depends on the small GTPase Rap2 and Hippo pathway and is not influenced by alteration of actin fibers. Deletion of Thbs1 in mice inhibited Thbs1/integrin ß1/YAP signaling, leading to maladaptive remodeling of the aorta in response to pressure overload and inhibition of neointima formation upon carotid artery ligation, exerting context-dependent effects on the vessel wall. We thus propose a mechanism of matrix mechanotransduction centered on Thbs1, connecting mechanical stimuli to YAP signaling during vascular remodeling in vivo.

Epithelial cell responses to rhinovirus identify an early-life-onset asthma phenotype in adults.

BACKGROUND: The study of pathogenic mechanisms in adult asthma is often marred by a lack of precise information about the natural history of the disease. Children who have persistent wheezing (PW) during the first 6 years of life and whose symptoms start before age 3 years (PW+) are much more likely to have wheezing illnesses due to rhinovirus (RV) in infancy and to have asthma into adult life than are those who do not have PW (PW-). OBJECTIVE: Our aim was to determine whether nasal epithelial cells from PW+ asthmatic adults as compared with cells from PW- asthmatic adults show distinct biomechanistic processes activated by RV exposure. METHODS: Air-liquid interface cultures derived from nasal epithelial cells of 36-year old participants with active asthma with and without a history of PW in childhood (10 PW+ participants and 20 PW- participants) from the Tucson Children's Respiratory Study were challenged with a human RV-A strain (RV-A16) or control, and their RNA was sequenced. RESULTS: A total of 35 differentially expressed genes involved in extracellular remodeling and angiogenesis distinguished the PW+ group from the PW- group at baseline and after RV-A stimulation. Notably, 22 transcriptomic pathways showed PW-by-RV interactions; the pathways were invariably overactivated in PW+ patients, and were involved in Toll-like receptor- and cytokine-mediated responses, remodeling, and angiogenic processes. CONCLUSIONS: Asthmatic adults with a history of persistent wheeze in the first 6 years of life have specific biomolecular alterations in response to RV-A that are not present in patients without such a history. Targeting these mechanisms may slow the progression of asthma in these patients.

Intravascular ultrasound insights into the unstable features of the coronary atherosclerotic plaques: A systematic review and meta-analysis.

BACKGROUND: There is a lack of a comprehensive picture of plaque geometry and composition of unstable atherosclerotic lesions as observed with intravascular ultrasound techniques. We analysed through a systematic review with meta-analysis 39 characteristics of atherosclerotic plaques in three scenarios involving culprit and non-culprit lesions from acute coronary syndromes vs stable angina pectoris patients, and culprit vs non-culprit lesions in acute coronary syndromes patients. METHODS: A systematic search of PubMed and EMBASE, from inception to April 2020 was performed. The combined odds ratios or mean differences of all IVUS characteristics were calculated with random-effects models. RESULTS: Twenty-eight studies involving 5434 subjects, and 5618 lesions were included. Culprit lesions in acute coronary syndromes have larger plaque areas and remodeling indexes (MD = 0.13 [0.08; 0.17], p < 0.001) and contained larger necrotic cores (MD = 0.67 (95% CI 0.19;1.15), p = 0.006) that stable angina culprit lesions. In acute patients, culprit plaques were also more remodeled, had larger necrotic cores and had more frequently a Thin-Cap Fibroatheroma morphology (OR = 1.79 (95% CI 1.21; 2.65), p = 0.004) than non-culprit lesions. Non-culprit lesions in acute syndromes were more often ruptured (OR = 2.25 (95% CI:1.05; 4.82), p = 0.037) or Thin-Cap Fibroatheromas than in stable angina. CONCLUSION: Culprit lesions from acute coronary patients are larger, more positively remodeled and contained more lipids as compared to stable angina lesions or non-culprit in acute patients. Non culprit lesions are also more often complicated or vulnerable in acute than stable patients.

Mechanical loading stimulates bone angiogenesis through enhancing type H vessel formation and downregulating exosomal miR-214-3p from bone marrow-derived mesenchymal stem cells.

Exosomes are important transporters of miRNAs, which play varying roles in the healing of the bone fracture. Angiogenesis is one of such critical events in bone healing, and we previously reported the stimulatory effect of mechanical loading in vessel remodeling. Focusing on type H vessels and exosomal miR-214-3p, this study examined the mechanism of loading-driven angiogenesis. MiRNA sequencing and qRT-PCR revealed that miR-214-3p was increased in the exosomes of the bone-losing ovariectomized (OVX) mice, while it was significantly decreased by knee loading. Furthermore, compared to the OVX group, exosomes, derived from the loading group, promoted the angiogenesis of endothelial cells. In contrast, exosomes, which were transfected with miR-214-3p, decreased the angiogenic potential. Notably, knee loading significantly improved the microvascular volume, type H vessel formation, and bone mineral density and contents, as well as BV/TV, Tb.Th, Tb.N, and Tb.Sp. In cell cultures, the overexpression of miR-214-3p in endothelial cells reduced the tube formation and cell migration. Collectively, this study demonstrates that knee loading promotes angiogenesis by enhancing the formation of type H vessels and downregulating exosomal miR-214-3p.

Hemodynamics and remodeling of the portal confluence in patients with malignancies of the pancreatic head: a pilot study towards planned and circumferential vein resections.

BACKGROUND: We designed a retrospective computational study to evaluate the effects of hemodynamics on portal confluence remodeling in real models of patients with malignancies of the pancreatic head. METHODS: Patient-specific models were created according to computed tomography data. Fluid dynamics was simulated by using finite-element methods. Computational results were compared to morphological findings. RESULTS: Five patients underwent total pancreatectomy, one had duodenopancreatectomy. Vein resection was performed en-bloc with the specimen. Histopathological findings showed that in patients without a vein stenosis and a normal hemodynamics, the three-layered wall of the vein was preserved. In patients with a stenosis > 70% of vein diameter and modified hemodynamics, the three-layered structure of the resected vein was replaced by a dense inflammatory infiltrate in absence of tumor infiltration. CONCLUSIONS: The portal confluence involved by malignancies of the pancreatic head undergoes a remodeling that is not mainly due to a wall infiltration by the tumor but instead to a persistent pathological hemodynamics that disrupts the balance between eutrophic remodeling and degradative process of the vein wall that can lead to the complete upheaval of the three-layered vein wall. This finding can have useful surgical application in planning resection of the vein involved by tumor growth.

Remodeling of occluded internal carotid artery in vessel wall magnetic resonance imaging.

OBJECTIVE: The purpose of the present study was to investigate the remodeling pattern of the extracranial occluded internal carotid artery (OICA) by vessel wall magnetic resonance imaging (VWI). METHODS: Thirty-nine atherosclerotic OICAs from 32 consecutive cases underwent 3-Tesla VWI to acquire pre- and post-contrast T1-weighted two-dimensional fluid-attenuated inversion recovery fast spin echo sequences. 25 symptomatic CAs exhibited ipsilateral downstream cerebral ischemia or ophthalmic artery embolism within last three months. The 14 remaining CAs were asymptomatic. Twenty-four CAs from 22 patients with atherosclerosis but no stenosis were recruited as control group. The outer wall area (OWA) was calculated based on the outer contour of the carotid artery drawn on the pre-contrast VWI. Negative remodeling was defined as a lower OWA compared to that of control group. RESULTS: Clinical characteristics including age, sex and vascular risk factors showed no significant difference between the occluded and control group. However, the OWA was lower in the occluded group than in the control group (0.63 versus 0.90 cm2, p = 0.004). For all OICAs, the OWA was larger in symptomatic cases than asymptomatic cases (0.71 versus 0.49cm2, p = 0.025). Using a cutoff value of 0.44, the sensitivity and specificity of OWA for detecting symptomatic OICA were 0.88 and 0.57, respectively. Heterogeneous signal intensity and enhancement were more often observed at the proximal than the distal segment of occlusion (p < 0.001). The inter-observer agreement regarding the evaluation of VWI characteristics was desirable (κ = 0.805 ∼ 0.847). CONCLUSIONS: Negative remodeling is prevalent in OICA, especially in asymptomatic cases.

A new intravascular ultrasound-guided stenting strategy compared with angiography on stent expansion and procedural outcomes in patients with positive lesion remodeling.

OBJECTIVES: We investigated the role of a new intravascular ultrasound (IVUS)-guided stenting strategy versus angiography on optimal stent expansion (OSE) and procedural outcomes in patients with positive lesion remodeling. BACKGROUND: There are no IVUS criteria on how to achieve OSE. METHODS: A total of 100 patients were assigned to a new IVUS-guided stenting strategy (IVUS group) versus angiography-guided stenting (Angio group). In the IVUS group, among patients with positive lesion remodeling, defined as a remodeling ratio (RR; lesion external elastic membrane (EEM) area/distal reference EEM area) >1.05, the stent was expanded with a balloon sized to the distal reference EEM diameter. In the Angio group, the stent was expanded by visual estimation. In both groups, IVUS was performed after postdilation. RESULTS: Minimum stent area (MSA) and stent volume index were significantly larger in the IVUS versus Angio group (7.1 ± 1.9 vs. 5.9 ± 1.5 mm2 , and 8.7 ± 2.1 vs. 7.5 ± 1.8 mm3 /mm, respectively; p < .01). The percentages of OSE, defined as an MSA ≥5.4 mm2 , MSA ≥90% of distal reference lumen area (DRLA), or MSA > DRLA, were significantly higher in the IVUS versus Angio group (80 vs. 56%, 78 vs. 54%, and 71 vs. 38%, respectively; p < .01). Stent underexpansion, malapposition, and residual reference segment stenosis were significantly higher in the Angio versus IVUS group (44 vs. 12%, 16 vs. 4%, and 12 vs. 0%, respectively; p < .05). In the IVUS group, owing to positive remodeling, there was no incidence of dissection or perforation. CONCLUSIONS: This new strategy of IVUS-guided stenting in patients with positive lesion remodeling, compared with angiography, significantly increased stent expansion and decreased stent underexpansion, malapposition, and residual reference segment stenosis with no complications.

Differential effects of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats.

Dexamethasone (DEX)-induced hypertension is observed in normotensive rats, but little is known about the effects of DEX on spontaneously hypertensive animals (SHR). This study aimed to evaluate the effects of DEX on hemodynamics, cardiac hypertrophy and arterial stiffness in normotensive and hypertensive rats. Wistar rats and SHR were treated with DEX (50 µg/kg s.c., 14 d) or saline. Pulse wave velocity (PWV), echocardiographic parameters, blood pressure (BP), autonomic modulation and histological analyses of heart and thoracic aorta were performed. SHR had higher BP compared with Wistar, associated with autonomic unbalance to the heart. Echocardiographic changes in SHR (vs. Wistar) were suggestive of cardiac remodeling: higher relative wall thickness (RWT, +28%) and left ventricle mass index (LVMI, +26%) and lower left ventricle systolic diameter (LVSD, -19%) and LV diastolic diameter (LVDD, -10%), with slightly systolic dysfunction and preserved diastolic dysfunction. Also, SHR had lower myocardial capillary density and similar collagen deposition area. PWV was higher in SHR due to higher aortic collagen deposition. DEX-treated Wistar rats presented higher BP (~23%) and autonomic unbalance. DEX did not change cardiac structure in Wistar, but PWV (+21%) and aortic collagen deposition area (+21%) were higher compared with control. On the other side, DEX did not change BP or autonomic balance to the heart in SHR, but reduced RWT and LV collagen deposition area (-12% vs. SHRCT ). In conclusion, the results suggest a differential effect of dexamethasone on arterial stiffness, myocardial remodeling and blood pressure between normotensive and spontaneously hypertensive rats.

Cyclo-oxygenase 2, a putative mediator of vessel remodeling, is expressed in the brain AVM vessels and associates with inflammation.

BACKGROUND: Brain arteriovenous malformations (bAVM) may rupture causing disability or death. BAVM vessels are characterized by abnormally high flow that in general triggers expansive vessel remodeling mediated by cyclo-oxygenase-2 (COX2), the target of non-steroidal anti-inflammatory drugs. We investigated whether COX2 is expressed in bAVMs and whether it associates with inflammation and haemorrhage in these lesions. METHODS: Tissue was obtained from surgery of 139 bAVMs and 21 normal Circle of Willis samples. The samples were studied with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR). Clinical data was collected from patient records. RESULTS: COX2 expression was found in 78% (109/139) of the bAVMs and localized to the vessels' lumen or medial layer in 70% (95/135) of the bAVMs. Receptors for prostaglandin E2, a COX2-derived mediator of vascular remodeling, were found in the endothelial and smooth muscle cells and perivascular inflammatory cells of bAVMs. COX2 was expressed by infiltrating inflammatory cells and correlated with the extent of inflammation (r = .231, p = .007, Spearman rank correlation). COX2 expression did not associate with haemorrhage. CONCLUSION: COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodelling and ongoing inflammation. Role of COX2 signalling in the pathobiology and clinical course of bAVMs merits further studies.

Broad-spectrum chemokine inhibition blocks inflammation-induced angiogenesis, but preserves ischemia-driven angiogenesis.

M3 is a broad-spectrum chemokine-binding protein that inactivates inflammatory chemokines, including CCL2, CCL5, and CX3CL1. The aim of this study was to compare whether M3 could inhibit angiogenesis driven by inflammation or ischemia. Here, apolipoprotein E-/- mice were injected with adenoviral M3 (AdM3) or control adenoviral green fluorescent protein (AdGFP) 3 d prior to stimulating angiogenesis using 2 established models that distinctly represent inflammatory or ischemia-driven angiogenesis, namely the periarterial femoral cuff and hind limb ischemia. AdM3 reduced intimal thickening, adventitial capillary density, and macrophage accumulation in femoral arteries 21 d after periarterial femoral cuff placement compared with AdGFP-treated mice (P < 0.05). AdM3 also reduced mRNA expression of proangiogenic VEGF, inflammatory markers IL-6 and IL-1ß, and vascular smooth muscle cell (VSMC)-activated synthetic markers Krüppel-like family of transcription factor 4 (KLF4) and platelet-derived growth factor receptor ß (PDGFRß) in the inflammatory cuff model. In contrast, capillary density, VSMC content, blood flow perfusion, and VEGF gene expression were unaltered between groups in skeletal muscle following hind limb ischemia. In vitro, AdM3 significantly reduced human microvascular endothelial cell 1 proliferation, migration, and tubule formation by ∼17, 71.3, and 8.7% (P < 0.05) in macrophage-conditioned medium associating with reduced VEGF and hypoxia-inducible factor 1α mRNA but not in hypoxia (1% O2). Compared with AdGFP, AdM3 also inhibited VSMC proliferation and migration and reduced mRNA expression of KLF4 and PDGFRß under inflammatory conditions. In contrast, AdM3 had no effect on VSMC processes in response to hypoxia in vitro. Our findings show that broad-spectrum inhibition of inflammatory chemokines by M3 inhibits inflammatory-driven but not ischemia-driven angiogenesis, presenting a novel strategy for the treatment of diseases associated with inflammatory-driven angiogenesis.-Ravindran, D., Cartland, S. P., Bursill, C. A., Kavurma, M. M. Broad-spectrum chemokine inhibition blocks inflammation-induced angiogenesis, but preserves ischemia-driven angiogenesis.

Investigating the Role of PPARß/δ in Retinal Vascular Remodeling Using Pparß/δ-Deficient Mice.

Peroxisome proliferator-activated receptor (PPAR)ß/δ is a member of the nuclear receptor superfamily of transcription factors, which plays fundamental roles in cell proliferation and differentiation, inflammation, adipogenesis, and energy homeostasis. Previous studies demonstrated a reduced choroidal neovascularization (CNV) in Pparß/δ-deficient mice. However, PPARß/δ's role in physiological blood vessel formation and vessel remodeling in the retina has yet to be established. Our study showed that PPARß/δ is specifically required for disordered blood vessel formation in the retina. We further demonstrated an increased arteriovenous crossover and wider venous caliber in Pparß/δ-haplodeficient mice. In summary, these results indicated a critical role of PPARß/δ in pathological angiogenesis and blood vessel remodeling in the retina.

Plaque modification and stabilization after paclitaxel-coated balloon treatment for de novo coronary lesions.

This study aimed to assess the healing response, as evidenced through temporal morphological and functional changes, following paclitaxel-coated balloon (PCB) treatment of de novo coronary lesions. This retrospective, observational study, included patients with significant de novo coronary lesions who were treated with PCB and had serial angiographic, intravascular ultrasound virtual histology (IVUS-VH), fractional flow reserve (FFR) measurements, and optical coherence tomography (OCT) performed before balloon angioplasty (BA), after BA, and at 9-month follow-up. A total of 20 patients (21 lesions) were included in this study. After PCB treatment, IVUS showed significant increases in the mean vessel area (12.0 ± 2.2 mm2 to 13.8 ± 2.5 mm2, p = 0.023), and mean lumen area (5.6 ± 1.2 mm2 to 7.0 ± 1.5 mm2, p = 0.003). Coronary flow was restored after BA with an FFR value of 0.87 ± 0.04 which was sustained at 9-month follow-up with no significant decrease (0.83 ± 0.08, p = 0.329). Serial OCT analysis showed that at 9-month follow-up dissections after BA sealed in 14 lesions (67%), whilst the macrophages decreased from 10 (50%) to 7 (35%) lesions, and the cap thickness of plaque increased from 0.12 ± 0.06 mm to 0.17 ± 0.09 mm (p = 0.007). PCB treatment for de novo coronary lesions showed persistent anatomical and functional patency at mid-term follow-up. Plaque modification, vascular remodeling, and plaque stabilization were also observed during follow-up.

Effect of Reverse Vessel Remodeling on Regression of Coronary Atherosclerosis in Patients Treated With Aggressive Lipid- and Blood Pressure-Lowering Therapy　- Insight From MILLION Study.

BACKGROUND: The MILLION study, a prospective randomized multicenter study, revealed that lipid and blood pressure (BP)-lowering therapy resulted in regression of coronary plaque as determined by intravascular ultrasound (IVUS). In the present study we performed additional analysis to investigate the associated factors with regression of coronary plaque.Methods and Results:We investigated serial 3D IVUS images from 68 patients in the MILLION study. Standard IVUS parameters were assessed at both baseline and follow-up (18-24 months). Volumetric data were standardized by length as normalized volume. In patients with plaque regression (n=52), plaque volumenormalizedsignificantly decreased from 64.8 to 55.8 mm3(P<0.0001) and vessel volumenormalizedsignificantly decreased from 135.0 to 127.5 mm3(P=0.0008). There was no difference in lumen volumenormalizedfrom 70.1 to 71.8 mm3(P=0.27). There were no correlations between % changes in vessel volume and cholesterol or BP. On the other hand, negative correlations between % change in vessel volume and vessel volumenormalizedat baseline (r=-0.352, P=0.009) or plaque volumenormalizedat baseline (r=-0.336, P=0.01) were observed. CONCLUSIONS: The current data demonstrated that in patients with plaque regression treated by aggressive lipid and BP-lowering therapy, the plaque regression was derived from reverse vessel remodeling determined by vessel volume and plaque burden at baseline irrespective of decreases in lipids and BP.

Tie1 is required for lymphatic valve and collecting vessel development.

Tie1 is a receptor tyrosine kinase with broad expression in embryonic endothelium. Reduction of Tie1 levels in mouse embryos with a hypomorphic Tie1 allele resulted in abnormal lymphatic patterning and architecture, decreased lymphatic draining efficiency, and ultimately, embryonic demise. Here we report that Tie1 is present uniformly throughout the lymphatics and from late embryonic/early postnatal stages, becomes more restricted to lymphatic valve regions. To investigate later events of lymphatic development, we employed Cre-loxP recombination utilizing a floxed Tie1 allele and an Nfatc1Cre line, to provide loxP excision predominantly in lymphatic endothelium and developing valves. Interestingly, unlike the early prenatal defects previously described by ubiquitous endothelial deletion, excision of Tie1 with Nfatc1Cre resulted in abnormal lymphatic defects in postnatal mice and was characterized by agenesis of lymphatic valves and a deficiency of collecting lymphatic vessels. Attenuation of Tie1 signaling in lymphatic endothelium prevented initiation of lymphatic valve specification by Prox1 high expression lymphatic endothelial cells that is associated with the onset of turbulent flow in the lymphatic circulation. Our findings reveal a fundamental role for Tie1 signaling during lymphatic vessel remodeling and valve morphogenesis and implicate it as a candidate gene involved in primary lymphedema.

M2 macrophage accumulation in the aortic wall during angiotensin II infusion in mice is associated with fibrosis, elastin loss, and elevated blood pressure.

Macrophages accumulate in blood vessels during hypertension. However, their contribution to vessel remodeling is unknown. In the present study, we examined the polarization state of macrophages (M1/M2) in aortas of mice during hypertension and investigated whether antagonism of chemokine receptors involved in macrophage accumulation reduces vessel remodeling and blood pressure (BP). Mice treated with ANG II (0.7 mg·kg(-1)·day(-1), 14 days) had elevated systolic BP (158 ± 3 mmHg) compared with saline-treated animals (122 ± 3 mmHg). Flow cytometry revealed that ANG II infusion increased numbers of CD45(+)CD11b(+)Ly6C(hi) monocytes and CD45(+)CD11b(+)F4/80(+) macrophages by 10- and 2-fold, respectively. The majority of macrophages were positive for the M2 marker CD206 but negative for the M1 marker inducible nitric oxide synthase. Expression of other M2 genes (arginase-1, Fc receptor-like S scavenger receptor, and receptor-1) was elevated in aortas from ANG II-treated mice, whereas M1 genes [TNF and chemokine (C-X-C motif) ligand 2] were unaltered. A PCR array to identify chemokine receptor targets for intervention revealed chemokine (C-C motif) receptor 2 (CCR2) to be upregulated in aortas from ANG II-treated mice, while flow cytometry identified Ly6C(hi) monocytes as the main CCR2-expressing cell type. Intervention with a CCR2 antagonist (INCB3344; 30 mg·kg(-1)·day(-1)), 7 days after the commencement of ANG II infusion, reduced aortic macrophage numbers. INCB334 also reduced aortic collagen deposition, elastin loss, and BP in ANG II-treated mice. Thus, ANG II-dependent hypertension in mice is associated with Ly6C(hi) monocyte and M2 macrophage accumulation in the aorta. Inhibition of macrophage accumulation with a CCR2 antagonist prevents ANG II-induced vessel fibrosis and elevated BP, highlighting this as a promising approach for the future treatment of vessel remodeling/stiffening in hypertension.

Post-angioplasty remodeling of coronary arteries investigated via a chemo-mechano-biological in silico model.

This work presents the application of a chemo-mechano-biological constitutive model of soft tissues for describing tissue inflammatory response to damage in collagen constituents. The material model is implemented into a nonlinear finite element formulation to follow up a coronary standard balloon angioplasty for one year. Numerical results, compared with available in vivo clinical data, show that the model reproduces the temporal dynamics of vessel remodeling associated with subintimal damage. Such dynamics are bimodular, being characterized by an early tissue resorption and lumen enlargement, followed by late tissue growth and vessel constriction. Applicability of the modeling framework in retrospective studies is demonstrated, and future extension towards prospective applications is discussed.

An arabinogalactan isolated from Cynanchum atratum promotes lymphangiogenesis and lymphatic vessel remodeling to alleviate secondary lymphedema.

Secondary lymphedema is a chronic and incurable disease lacking satisfactory therapeutic drugs. It primarily results from lymphatic vessel dysfunction resulting from factors such as tumor-related surgery, injury, or infection. Promoting lymphangiogenesis and lymphatic vessel remodeling is crucial for restoring tissue fluid drainage and treating secondary lymphedema. In this study, we discovered that the oral administration of a type-II arabinogalactan (CAPW-1, molecular weight: 64 kDa) significantly promoted lymphangiogenesis and alleviated edema in mice with secondary lymphedema. Notably, the tail diameter of the CAPW-1200 group considerably decreased in comparison to that of the lymphedema group, with an average diameter difference reaching 0.98 mm on day 14. CAPW-1 treatment also reduced the average thickness of the subcutaneous area in the CAPW-1200 group to 0.37 mm (compared with 0.73 mm in the lymphedema group). It also facilitated the return of injected indocyanine green (ICG) from the tail tip to the sciatic lymph nodes, indicating that CAPW-1 promoted lymphatic vessel remodeling at the injury site. In addition, CAPW-1 enhanced the proliferation and migration of lymphatic endothelial cells. This phenomenon was associated with the activation of the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway, thereby promoting the expression of vascular endothelial growth factor-C (VEGF-C), which can be abolished using a TLR4 antagonist. Despite these findings, CAPW-1 did not alleviate the symptoms of lymphedema or restore lymphatic drainage in VEGFR3flox/flox/Prox1-CreERT2 mice. In summary, CAPW-1 alleviates secondary lymphedema by promoting lymphangiogenesis and lymphatic vessel remodeling through the activation of the TLR4/NF-κB/VEGF-C signaling pathway, indicating its potential as a therapeutic lymphangiogenesis agent for patients with secondary lymphedema.

A Microphysiological Model to Mimic the Placental Remodeling during Early Stage of Pregnancy under Hypoxia-Induced Trophoblast Invasion.

Placental trophoblast invasion is critical for establishing the maternal-fetal interface, yet the mechanisms driving trophoblast-induced maternal arterial remodeling remain elusive. To address this gap, we developed a three-dimensional microfluidic placenta-on-chip model that mimics early pregnancy placentation in a hypoxic environment. By studying human umbilical vein endothelial cells (HUVECs) under oxygen-deprived conditions upon trophoblast invasion, we observed significant HUVEC artery remodeling, suggesting the critical role of hypoxia in placentation. In particular, we found that trophoblasts secrete matrix metalloproteinase (MMP) proteins under hypoxic conditions, which contribute to arterial remodeling by the degradation of extracellular matrix components. This MMP-mediated remodeling is critical for facilitating trophoblast invasion and proper establishment of the maternal-fetal interface. In addition, our platform allows real-time monitoring of HUVEC vessel contraction during trophoblast interaction, providing valuable insights into the dynamic interplay between trophoblasts and maternal vasculature. Collectively, our findings highlight the importance of MMP-mediated arterial remodeling in placental development and underscore the potential of our platform to study pregnancy-related complications and evaluate therapeutic interventions.