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Following the placement of endovascular implants, perivascular adipose tissue (PVAT) becomes an early sensor of vascular injury to which it responds by undergoing phenotypic changes characterized by reduction in the secretion of adipocyte-derived relaxing factors and a shift to a proinflammatory and pro-contractile state. Thus, activated PVAT loses its anti-inflammatory function, secretes proinflammatory cytokines and chemokines, and generates reactive oxygen species, which are accompanied by differentiation of fibroblasts into myofibroblasts and proliferation of smooth muscle cells. These subsequently migrate into the intima, leading to intimal growth. In addition, periadventitial vasa vasorum undergoes neovascularization and functions as a portal for extravasation of inflammatory infiltrates and mobilization of PVAT resident stem/progenitor cells into the intima. This review focuses on the response of PVAT to endovascular intervention-induced injury and discusses potential therapeutic targets to suppress the PVAT-initiated pathways that mediate the formation of neointima., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Vascular scaffold implantation induces injury to the intimal layer and causes discontinuity of the regenerated endothelial monolayer, compromising barrier integrity, increasing permeability, and allowing the transmigration of leukocytes and lipoproteins into the subendothelial space. Mechanical vascular wall stretching triggers Ras homolog family member A (RhoA)/Rho kinase-mediated actomyosin contractility and destabilization of adherens junctions, leading to endothelial barrier dysfunction. Assembly of intercellular adhesion and actin cytoskeletal organization of interendothelial junctions are controlled by downregulation of RhoA guanosine triphosphatase (GTPase)-mediated barrier-disruptive activity and upregulation of repressor-activator protein 1 (Rap1) and Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase-mediated cytoskeletal reorganization, leading to endothelial barrier stabilization. This review highlights the involvement of Rho GTPases in the disruption of endothelial barrier integrity following vascular scaffold implantation and the targeting of downstream Rho-associated protein kinases, which signal the network to restore endothelial barrier integrity and stability., (Published by Elsevier Ltd.)

Tamarindus indica is a multipurpose dry land species in sub-Saharan that is traditionally used to build resilience into the farming system. The species is highly threatened and listed on the IUCN Red List. However, information on how climatic condition locally influences its ecological distribution is limited. This study investigates the current and future suitable habitat for the species in the Tigray region, in northern Ethiopia. A total of 220 species presence points and the number of T. indica within a 50 m × 50 m plot were collected. In addition, 19 bioclimatic variables, 3 topographic variables and soil data were used to model the impact of future climate conditions under two Representative Concentration Path Ways (RCP4.5 and RCP 8.5). MaxEnt-v-3.3.3 k, Diva-GIS-7.5, and GIS10.6 were used to model the current and future distribution. SPSSv-26 was also utilized to analyze the relationship between the species' abundance and environmental variables. Results showed that the environmental variables determining most for the distribution of T. indica were mean diurnal range (Bio2 (56.9%)); temperature seasonality (Bio4 (10.3%)) and temperature annual range (Bio7 (9.2%)). The model suggested that the current distribution of T. indica covers an area of 9209 km 2 (14.04%). This would have increased to 29,363 km 2 (44.78%) and 11,046 km 2 (16.85%) by 2070 under RCP4.5 and RCP8.5, respectively. Compared to the high-impact areas, new gains of suitable areas (net 25,081 km 2 ) for the future distribution of the species were predicted in 2070-RCP4.5. Altitude, rainfall, temperature, silt contents of soils and soil pH have significant contributions (P-value<0.05) to the abundance of T. indica . However, altitude has a negative relationship with the abundance of T. indica . Additional studies to understand population trends and other threats are recommended., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Activated platelets coat circulating tumor cells, protecting them from shear stress in the blood stream and promoting their evasion from immune surveillance. Platelets promote tumor cell dissemination to distant organs by releasing transforming growth factor-β1 (TGF-β1) into the tumor microenvironment, which induces phenotypic changes to the epithelial-mesenchymal transition. This process facilitates tumor cell transendothelial extravasation and formation of early metastatic niches. Development of antiplatelet agents that interrupt the platelet-tumor cell axis but do not interfere with physiological hemostatic mechanisms is critical. The glycoprotein VI (GPVI), a member of the immunoreceptor family that is co-expressed with the fragment crystallizable (Fc) receptor γ-chain, is exclusively expressed in platelets and megakaryocytes, and blocking the receptor or genetic deficiency has minimal impact on bleeding. Tumor cell-expressed galectin-3, which contains a collagen-like peptide domain, binds to platelet GPVI-dimers, and the receptor-ligand activates platelets to form a protective heteroaggregate coat around tumor cells. This review highlights the potential of targeting the GPVI/FcR γ-chain complex to inhibit platelet activation by galectin-3 expressing tumor cells, disrupting the platelet-tumor cell amplification loop while maintaining the function of platelets in hemostasis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Neonatal megakaryopoiesis and platelet turnover form a developmentally unique pattern by generating a pool of newly released reticulated platelets from the bone marrow into the circulation. Reticulated platelets are more reactive and hyperaggregable compared to mature platelets, due to their high residual mRNA content, large size, increased expression of platelet surface receptors, and degranulation. The proportion of reticulated platelets in neonates is higher compared to that in adults. Due to the emergence of an uninhibited platelet subpopulation, the newly formed reticulated platelet pool is inherently hyporesponsive to antiplatelets. An elevated population of reticulated platelets is often associated with increased platelet reactivity and is inversely related to high on-treatment platelet reactivity, which can contribute to ischemia. Measurements of the reticulated platelet subpopulation could be a useful indicator of increased tendency for platelet aggregation. Future research is anticipated to define the distinct functional properties of newly formed reticulated or immature platelets in neonates, as well as determine the impact of enhanced platelet turnover and high residual platelet reactivity on the response to antiplatelet agents.

Abstract: Endothelial cells adhere to one another through junctional structures formed by intercellular adhesion molecules. These intercellular proteins regulate barrier function in response to the hemodynamic shear rate and enable the selective passage of solutes and fluids across the endothelium. After endovascular device implantation, the endothelial barrier is compromised and becomes discontinuous, which increases permeability, allowing transmigration of leukocytes and lipoproteins and leading to the accumulation of lipid-laden foamy macrophages in the subendothelial space. Drug-coated bioresorbable vascular scaffold implants have been associated with unexpected thrombotic complications, which were not predicted in animals because of dissimilarities in endothelial regeneration and realignment between animals and humans. The development of a microengineered, microfluidics-based system of patterned channels lined with human endothelial and smooth muscle cells perfused with blood allows for the evaluation of endothelial function and barrier integrity. This review highlights the translational potential of vasculature-on-chip, which recreates the microphysiological milieu to evaluate the impact of drug-eluting bioresorbable vascular scaffolds on endothelial barrier integrity and to characterize polymer biodegradation behavior and drug release kinetic profiles over time., Competing Interests: The author reports no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Agroforestry (AF) is an ancient tradition in Ethiopian dryland farming system. Several studies have examined system design, soil fertility management and system interactions, but the biodiversity and mitigation aspects of climate change have received less focus. We assessed the diversity of woody species, biomass carbon (C), and soil organic carbon (SOC) stock associated with indigenous dryland AF practices. A total of 197 smallholder farmers representing four AF practices (home garden, parkland, boundary plantation, and woodlot) from lowland, midland, and highland areas were systematically selected. The inventory of woody species was carried out on each farm's randomly formed plot., Results: We identified a total of 59 woody species representing 48 genera and 32 families. Shannon diversity index (H') was highest in home garden and parkland AF, while woodlots had the highest mean total stock of biomass C (31 Mg C ha -1 ). C stocks for smallholding systems (total biomass C and SOC 0-60 cm) ranged from 77-135 Mg ha -1 . Total biomass C stocks were significantly correlated with abundance (Spearman r = 0.333; p = 0.002) but biomass components were not significantly correlated with H'. SOC soil depth stock (0-60 cm) was positively and significantly associated with H' (Spearman r = 0.291 & 0.351; p < 0.01)., Conclusions: We report greater species richness in home garden and parkland AF systems than in woodlots. While parkland AF produce lower biomass and SOC stock relative to other AF systems. The strategic use of home gardens and boundary planting can improve tree diversity and carbon storage in Ethiopian dryland ecosystems.

The enzyme soluble guanylate cyclase (sGC) plays an essential part in the nitric oxide (NO) signaling pathway by binding to the prosthetic heme group; thereby catalyzing the synthesis of cyclic guanosine monophosphate (cGMP)-dependent protein kinases. Impaired NO-sGC-cGMP signaling could lead to osteoblast apoptosis by mechanisms involving the oxidative-stress-induced shift of the redox state of the reduced heme to oxidized sGC, leading to diminished heme binding to the enzyme and rendering the sGC unresponsive to NO. Targeting oxidized sGC to enhance cGMP production could restore proliferation and differentiation of osteoblasts into osteocytes. Here, the potential role of sGC activators of an oxidized or heme-free sGC as a target for promoting osteoblast function is reviewed and strategies for delivering drugs to bone are identified., (Published by Elsevier Ltd.)

Vascular calcification results from an imbalance of promoters and inhibitors of mineralization in the vascular wall, culminating in the creation of an organized extracellular matrix deposition. It is characterized by the accumulation of calcium phosphate complex and crystallization of hydroxyapatite in the tunica media, leading to vessel stiffening. The underlying initiators of dysregulated calcification maintenance are diverse. These range from the expression of bone-associated proteins, to the osteogenic transdifferentiation of smooth muscle cells to osteoblast-like cells, to the release of fragmented apoptotic bodies and mineralization competent extracellular vesicles by smooth muscle cells, which act as a nucleation site for the deposition of hydroxyapatite crystals. The process involves a complex interplay between vitamin K-dependent calcification-inhibitory proteins, such as matrix γ-carboxyglutamate acid (Gla) protein, Gla-rich protein and growth arrest-specific gene 6 protein, and stimulatory mediators, such as osteocalcin. Vitamin K plays an important role as a cofactor for posttranslational γ-carboxylation of matrix Gla proteins in converting to a biologically active conformation. Drugs that inhibit vitamin K, such as warfarin, impair γ-carboxylation of Gla proteins, resulting in the accumulation of uncarboxylated proteins lacking calcification-inhibitory capacity. This article overviews the involvement of systemically and locally expressed vitamin K-dependent proteins in vascular calcification and their potential as biomarkers of calcification.

Bioresorbable scaffolds have emerged as a potential alternative to non-erodible metal implants to alleviate the long-term risk of permanent device vascular implant-related adverse events. Bioresorbable scaffolds provide a temporary mechanical support function until the vessel reaches complete healing, and the implant progressively disappears and vasomotion resumes. A polymer matrix with embedded drugs coated onto the scaffold surface degrades slowly, reducing the size from the exterior toward the interior, and this allows controlled drug release to a local vascular segment. Drug elution from a bioresorbable scaffold system is characterized by a rapid initial release that achieves high concentration along the intimal surface, which is designed to prevail vascular dilation-induced injury and formation of neointimal hyperplasia. This review highlights diverse types of bioresorbable biomaterials as vascular scaffolds, drug release kinetics, adaptive arterial wall remodeling, and complexities in the advancement of vascular scaffolds to treat restenosis.

The adventitia functions as a dynamic compartment for cell trafficking into and out of the artery wall, and communicates with medial and intimal cells. The resident cells in the tunica adventitia play an integral role in the regulation of vessel wall structure, repair, tone, and remodeling. Following injury to the vascular wall, adventitial fibroblasts are activated, which proliferate and differentiate into migratory myofibroblasts, and initiate inflammation through the secretion of soluble factors such as chemokines, cytokines, and adhesion molecules. The secreted factors subsequently promote leukocyte recruitment and extravasation into the media and intima. The adventitia generates reactive oxygen species and growth factors that participate in cell proliferation, migration, and hypertrophy, resulting in intimal thickening. The adventitial vasa vasorum undergoes neovascularization and serves as a port of entry for the delivery of inflammatory cells and resident stem/progenitor cells into the intima, and thus facilitates vascular remodeling. This review highlights the contribution of multilineage cells in the adventitia along with de-differentiated smooth muscle-like cells to the formation of neointimal hyperplasia, and discusses the potential of periadventitial local drug delivery for the prevention of vascular restenosis., (Published by Elsevier Inc.)

Platelets undergo a process of developmental maturation, and hence its regulation of vascular integrity and control of hemostasis at various stages of neonatal ages deserves better characterization. Functional assays for platelets require a larger volume of blood than what is feasible to collect in neonates, creating a technical hurdle that has been a challenge to investigate neonatal platelets. For this reason, the current knowledge of neonatal platelet function has been based on studies from cord blood-derived platelets as a surrogate for neonatal peripheral blood. Studies indicate that neonatal platelets are hypofunctional to various agonists, although neonates tend to maintain normal hemostasis. This apparently paradoxical finding may be due to several factors, such as elevated functionally potent von Willebrand factor multimers or hematocrit levels, in the neonatal blood that enhance the platelet and vessel wall interaction, and counteract platelet hyporeactivity. This review describes the functional characteristics of neonatal platelets, differences in platelet reactivity between neonates and adults, and potential biomarkers of platelet activation., (Published by Elsevier Ltd.)

Balloon-based drug delivery systems allow localized application of drugs to a vascular segment to reduce neointimal hyperplasia and restenosis. Drugs are coated onto balloons using excipients as drug carriers to facilitate adherence and release of drug during balloon inflation. Drug-coated balloon delivery system is characterized by a rapid drug transfer that achieves high drug concentration along the vessel wall surface, intended to correspond to the balloon dilation-induced vascular injury and healing processes. The balloon catheter system allows homogenous drug delivery to the vessel wall, such that the drug release per unit surface area is kept constant along balloons of different lengths. Optimization of the balloon coating matrix is essential for efficient drug transfer and tissue retention until the artery remodels to a normal set point. Challenges in the development of balloon-based drug delivery to the arterial wall include finding suitable excipients for drug formulation to enable drug release to a targeted lesion site effectively, maintain coating integrity during transit, prolong tissue retention and reduce particulate generation. This review highlights various factors involved in the successful design of balloon-based delivery systems, including drug release kinetics, matrix coating transfer, transmural drug partitioning, dissolution rate and release of unbound active drug., (Published by Elsevier B.V.)

The metallic stents with durable polymers have been effective in reducing the need for revascularization, but the permanent presence of the metal and polymer have been associated with persistent inflammation, hypersensitivity reactions and incidence of thrombosis. Recent innovations of bioresorbable polymers are in development which could serve as temporary scaffolds that degrade into molecules and eventually resorb overtime, and leave the artery free of any permanent prosthetic constraints. The transient scaffolding has the advantages of restoring blood vessel to natural state, improve vasomotor tone and increase lumen enlargement because of expansive remodeling following completion of polymer resorption. The success of bioresorbable vascular scaffolds will depend on the degradation timeline, such that the elastic recoil of the blood vessel and negative remodeling which could potentially lead to restenosis are prevented. Bioresorbable scaffolds with bulky backbone and thick struts could lead to prolonged biodegradation, alter blood flow dynamics and increase thrombogenicity. The development of bioresorbable scaffolds is challenging because of the complexity of finding an ideal balance of polymer biodegradation and controlled drug release over time, such that the fractional drug released achieves optimal inhibitory concentration until the blood vessel remodels to a stable set point. This review discusses the various types of biodegradable materials, factors affecting biodegradation, drug release kinetics, vascular biocompatibility, adaptive vascular remodeling, and challenges in the development of bioresorbable scaffolds to treat vascular restenosis., (Published by Elsevier Ltd.)

Coronary artery intervention using device implants significantly reduce the risk of restenosis and the need for revascularization but are associated with endothelial denudation and impaired function. This may be due to incomplete endothelial recovery as a result of intimal injury, presence of polymer and/or high antiproliferative drug accumulation in the intima. The permanent presence of a metal prosthesis or polymer may impair the proliferation of resident endothelial cells to cover empty areas. Attention has focused on the robust replenishment of endothelial monolayer by recruitment of circulating endothelial progenitor cells derived from the bone marrow to areas of endothelial injury. The balance between endothelial damage and repair is critical for the maintenance of intimal integrity, function, and prevention of thrombotic complications. This review will discuss on the aftereffects of intravascular device implants on endothelial injury and the pathways involved in endothelial repair and regeneration with an emphasis on endothelial progenitor cells.

Extensive experimental evidence indicates that platelets contribute to tumor cell proliferation and metastasis through direct interactions and secreted bioactive proteins. Activated platelets release secretory factors that promote growth factors, chemokines, proangiogenic regulatory proteins, proteolytic enzymes and microparticles within the microenvironment to promote tumor cell growth and invasion. Furthermore, the formation of platelet-tumor cell heteroaggregates by integrin αIIbβ3 (glycoprotein IIb/IIIa) bridging plays an important role in tumor survival by forming a physical shield around tumor cells, and thereby protecting circulating tumor cells from immune-mediated lysis by natural killer (NK) cells. Tumor cells directly activate platelets by enhancing expression of surface integrins, selectins and secretion of granules, which amplify platelet aggregation. In addition to the physical coating of tumor cells, platelets release transforming growth factor-β1 (TGF-β1) that induces phenotypic changes of epithelial to mesenchymal-like transition of tumor cells, thereby facilitating their extravasation and dissemination to distant sites during metastasis. Thus, there is a complex interplay between platelet-induced tumor growth and tumor cell-induced platelet activation, with the involvement of multiple components within the tumor microenvironment that enhance metastasis. This review describes the intimate reciprocal cross-talk between platelets and tumor cells, and the various signaling pathways involved in tumor amplification, which may be potential therapeutic targets to disrupt the platelet-tumor loop to reduce metastatic processes., (Published by Elsevier Inc.)