Targeting glycoprotein VI to disrupt platelet-mediated tumor cell extravasation.

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-ß1 (TGF-ß1) 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.

Vasculature-on-chip for Assessment of Bioresorbable Scaffolds and Endothelial Barrier Integrity.

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.

Distinct characteristics of neonatal platelet reactivity.

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.

Bioresorbable vascular scaffolds: Biodegradation, drug delivery and vascular remodeling.

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.

Nonclinical aspects of venous thrombosis in pregnancy.

Pregnancy is a hypercoagulable state which carries an excess risk of maternal venous thrombosis. Endothelial injury, alterations in blood flow and activation of the coagulation pathway are proposed to contribute to the hypercoagulability. The risk for thrombosis may be accentuated by certain drugs and device implants that directly or indirectly affect the coagulation pathway. To help ensure that these interventions do not result in adverse maternal or fetal outcomes during pregnancy, gravid experimental animals can be exposed to such treatments at various stages of gestation and over a dosage range that would identify hazards and inform risk assessment. Circulating soluble biomarkers can also be evaluated for enhancing the assessment of any increased risk of venous thrombosis during pregnancy. In addition to traditional in vivo animal testing, efforts are under way to incorporate reliable non-animal methods in the assessment of embryofetal toxicity and thrombogenic effects. This review summarizes hemostatic balance during pregnancy in animal species, embryofetal development, biomarkers of venous thrombosis, and alterations caused by drug-induced venous thrombosis.

Impact of Perivascular Adipose Tissue on Neointimal Formation Following Endovascular Placement.

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.

Targeting Rho kinase to restore endothelial barrier function following vascular scaffold implantation.

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.

Optimization of preparation parameters of ceramic pot water filters for potential application of microbial and fluoride removal from groundwater.

The need to make clean water accessible and affordable for low-income countries is crucial. This study examines the suitability of various clays for Ceramic Pot Water Filters production and groundwater treatment for effective microbe and fluoride removal. For this study, three clays were collected from different geographical locations in Ethiopia,i.e., Hosaenna Clay, Babawuha Clay, and Leku Clay. Organic additives such as sawdust and eragrostis tef husks were used to increase the porosity of the Ceramic Pot Water Filters. The Atterberg limit and particle size distribution tests revealed that BC and HC have moderate to high plasticity and mouldability, making them suitable for CPWF production. The clay chemical composition, phase analysis, and thermal properties were determined using XRF, XRD, and TGA/DTA. The turbidity, fluoride level, total dissolved solids, and pH of the groundwater decreases, from 13 to 0.45 NTU, from 3.4 to 0.053 mg/100 mL, from 1245 to 360 mg/l, and from 8.4 to 7.3, respectively; all of which are within the acceptable range of WHO drinking water standards. Microbial removal tests show that the CPWFs removed 99.3%-100% of total coliform bacteria and 98.48%-100% of fecal coliform bacteria from groundwater. Therefore, this work paves the way to fabricate a clay-based ceramic water filter for low-income countries to provide affordable household groundwater treatment technology for microbial and excess fluoride removal.

Investigation of Self-Healing Mortars with and without Bagasse Ash at Pre- and Post-Crack Times.

Cracks in typical mortar constructions enhance water permeability and degrade ions into the structure, resulting in decreased mortar durability and strength. In this study, mortar samples are created that self-healed their cracks by precipitating calcium carbonate into them. Bacillus subtilus bacterium (10-7, 10-9 cells/mL), calcium lactate, fine aggregate, OPC-cement, water, and bagasse ash were used to make self-healing mortar samples. Calcium lactates were prepared from discarded eggshells and lactic acid to reduce the cost of self-healing mortars, and 5% control burnt bagasse ash was also employed as an OPC-cement alternative. In the presence of moisture, the bacterial spores in mortars become active and begin to feed the nutrient (calcium lactate). The calcium carbonate precipitates and plugs the fracture. Our experimental results demonstrated that cracks in self-healing mortars containing bagasse ash were largely healed after 3 days of curing, but this did not occur in conventional mortar samples. Cracks up to 0.6 mm in self-healing mortars were filled with calcite using 10-7 and 10-9 cell/mL bacteria concentrations. Images from an optical microscope, X-ray Diffraction (XRD), and a scanning electron microscope (SEM) were used to confirm the production of calcite in fractures. Furthermore, throughout the pre- and post-crack-development stages, self-healing mortars have higher compressive strength than conventional mortars. The precipitated calcium carbonates were primed to compact the samples by filling the void spaces in hardened mortar samples. When fissures developed in hardened mortars, bacteria became active in the presence of moisture, causing calcite to precipitate and fill the cracks. The compressive strength and flexural strength of self-healing mortar samples are higher than conventional mortars before cracks develop in the samples. After the healing process of the broken mortar parts (due to cracking), self-healing mortars containing 5% bagasse ash withstand a certain load and have greater flexural strength (100 kPa) than conventional mortars (zero kPa) at 28 days of cure. Self-healing mortars absorb less water than typical mortar samples. Mortar samples containing 10-7 bacteria cells/mL exhibit greater compressive strength, flexural strength, and self-healing ability. XRD and SEM were used to analyze mortar samples with healed fractures. XRD, FTIR, and SEM images were also used to validate the produced calcium lactate. Furthermore, the durability of mortars was evaluated using DTA-TGA analysis and water absorption tests.

Induction of nicotinamide-adenine dinucleotide phosphate oxidase and apoptosis by biodegradable polymers in macrophages: implications for stents.

The drug-eluting stent platform has a limited surface area, and a polymer carrier matrix is coated to enable sufficient loading of drugs. The development of a suitable polymer has been challenging because it must exhibit biocompatibility with the intravascular milieu. The use of biodegradable polymers seems to be attractive because it enables drug release as it degrades and is eventually eliminated from the body leaving the permanent metallic stent polymer-free. The aim of this study was to investigate the biocompatibility of biodegradable polymers using the human monocyte cell line. Cultured monocytes differentiated into functional macrophages (THP-1) were incubated with various polymers including poly-L-lactide (PLA), polycaprolactone (PCL), or poly-D, L-lactide-co-glycolide (PLGA) for up to 5 days. Exposure of cells to the polymers resulted in macrophage-polymer adhesion and induced marked pro-oxidant species as measured by calcein AM uptake assay and flow cytometric analysis of 2',7'-dichlorofluorescin fluorescence, respectively. Real-time reverse-transcription polymerase chain reaction and Western blot analysis of expression of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases revealed enhanced expression of NADPH oxidase subunits in response to PLA and PLGA compared with that of PCL. Flow cytometric analysis of fluorescein isothiocyanate-Annexin V and propium iodide-stained PLA and PGLA polymer-exposed THP-1 cells showed early and late apoptotic changes. Similarly, exposure to the PLA and PGLA polymers, but not to the PCL polymer, resulted in enhanced staining for cleaved poly(ADP-ribose) polymerase-1, a protein fragment produced by caspase cleavage. These results indicate that biodegradable polymers are associated with cell adhesion, NADPH oxidase-induced generation of reactive oxygen species and excess apoptosis.

Impact of Reticulated Platelets on Platelet Reactivity in Neonates.

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.

Investigation on Control Burned of Bagasse Ash on the Properties of Bagasse Ash-Blended Mortars.

In recent years, partial replacement of cement with bagasse ash has been given attention for construction application due to its pozzolanic characteristics. Sugarcane bagasse ash and fine bagasse particles are abundant byproducts of the sugar industries and are disposed of in landfills. Our study presents the effect of burning bagasse at different temperatures (300 °C and 600 °C) on the compressive strength and physical properties of bagasse ash-blended mortars. Experimental results have revealed that bagasse produced more amorphous silica with very low carbon contents when it was burned at 600 °C/2 h. The compressive strength of mortar was improved when 5% bagasse ash replaced ordinary portland cement (OPC) at early curing ages. The addition of 10% bagasse ash cement also increased the compressive strength of mortars at 14 and 28 days of curing. However, none of the bagasse ash-blended portland pozzolana cement (PPC) mortars have shown improvement on compressive strength with the addition of bagasse ash. Characterization of bagasse ash was done using XRD, DTA-TGA, SEM, and atomic absorption spectrometry. Moreover, durability of mortars was checked by measuring water absorption and apparent porosity for bagasse ash-blended mortars.

Paclitaxel potentiates inflammatory cytokine-induced prothrombotic molecules in endothelial cells.

To overcome the limitations of balloon expandible metal stent-induced neointimal smooth muscle cell proliferation, drug-coated stent devices have been developed. Drug eluting stents release high concentrations of antiproliferative agents, such as paclitaxel, to reduce neointimal hyperplasia. The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), is known to cause severe endothelial dysfunction and accelerate atherosclerotic lesion progression. The interaction of TNF-alpha and paclitaxel on the release of prothrombotic molecules was examined in endothelial cells. Treatment of endothelial cells with paclitaxel had no direct effect on tissue factor (TF) expression, but TNF-alpha increased TF. Cotreatment of paclitaxel with TNF-alpha markedly augmented the release of TF. TNF-alpha induced release of plasminogen activator inhibitor but no synergism occurred with paclitaxel. Treatment of endothelial cells with paclitaxel and TNF-alpha reduced expression of thrombomodulin and protein C receptor. Tissue factor pathway inhibitor expression was reduced by prolonged treatment with either paclitaxel or TNF-alpha. The adhesion molecule, CD62 E, was induced by TNF-alpha; however, CD31, CD62 P, and CD106 were not affected by paclitaxel and TNF-alpha. Apoptosis was not observed with cotreatment of endothelial cells with paclitaxel and TNF-alpha. CD59-positive microparticles were released in response to TNF-alpha, but the release was not augmented by paclitaxel. Paclitaxel and TNF-alpha increased the nitrotyrosination of proteins. These findings indicate that paclitaxel enhances TNF-alpha-induced release of TF, and downregulated thrombomodulin, increased protein nitration, which may subsequently favor prothrombotic intimal surface.

Targeting heme-oxidized soluble guanylate cyclase to promote osteoblast function.

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.

Involvement of Vitamin K-Dependent Proteins in Vascular Calcification.

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 Scaffold-Based Controlled Drug Delivery for Restenosis.

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.

Platelet function in intravascular device implant-induced intimal injury.

Platelets are involved in the rapid response to intimal injury in which the underlying thrombogenic subendothelial matrix is exposed, leading to platelet adhesion, secretion, aggregation, and initiation of arterial thrombus formation. The platelet activation pathway involves a multistep process of distinct receptors, adhesive ligands, release of mediators, receptor-ligand interactions, and recruitment of more platelets to the site of injury. The balance between blood fluidity and intimal injury-induced arterial thrombosis is maintained by an intact endothelium that controls vessel tone, synthesizes inhibitors and activators of platelet function, and thereby allows the free flow of blood cell elements. An intravascular device implant causes intimal injury, which is accompanied by decreased antithrombotic potential of the endothelial cells and increased release of prothrombotic substances. A trigger for the formation of intimal injury-induced thrombus formation may be due to endothelial dysfunction and/or the loss of endothelial cell barrier between the subendothelial matrix and flowing blood, which allows initiation of platelet activation. A thorough understanding of the platelet regulatory mechanisms is necessary to develop effective antiplatelet therapy to prevent the complications of thrombosis following revascularization procedures using percutaneous coronary intervention. This review summarizes the temporal events following intravascular device implants, including endothelial cell injury, platelet activation, receptor-mediated signaling events, platelet-rich thrombus formation, and the redundant platelet pathways, all of which may be potential therapeutic targets.

Endothelial injury in the initiation and progression of vascular disorders.

Endothelial cell dysfunction is considered to be an early event which subsequently leads to vascular wall disorders. Ultrastructural studies indicate that the endothelial cell changes involve membrane damage, increased permeability, swelling and necrosis. The endothelial cell loss of function could be as a result of changes in hemodynamic forces (shear and/or hoop stress), direct drug-induced cytotoxicity, mechanical device implant-induced injury and/or immune-mediated mechanisms. Drugs may perturb endothelial cell integrity by directly triggering inflammatory signaling cascades, enhancing expression of cellular adhesion molecules, activation of cytotoxic T cells and/or autoantibodies directed against endothelial cell membranes. Local release of inflammatory cytokines and chemokines activate endothelial cells to upregulate soluble adhesion molecules, activate neutrophils and generate reactive oxygen species which serve to amplify the initial inflammation leading to dysregulated apoptosis, secondary necrosis and overt vascular injury lesions. Considering the role of the endothelium in the initiation and propagation of vascular wall injury, there is a need for the discovery of validated biomarkers to serve as a predictor of activation of inflammatory cascades in the development of vascular injury. This article reviews some aspects of the multifaceted mechanisms that lead to the initial endothelial cell disruption and subsequent vascular wall injury.

Local vascular toxicokinetics of stent-based drug delivery.

One of the major limitations of balloon angioplasty is early restenosis as a result of elastic recoil leading to vessel occlusion. The constrictive (negative) remodeling of the blood vessel is overcome by implanting a balloon expandible metal stent to dilate the artery and thereby prevent elastic recoil. However, bare metal stent implants cause mechanical injury to the intima and release of inflammatory mediators which then initiates formation of neointimal layer leading to restenosis. In-stent restenosis is histologically distinct from restenosis following balloon angioplasty, in which in-stent restenosis is accompanied by increased smooth muscle proliferation, migration, extracellular matrix and collagen synthesis leading to neointimal hyperplasia. To overcome neointimal hyperplasia, stents have been coated with pharmacological agents that inhibit smooth muscle cell proliferation and migration. The drug and polymer combination coated onto stent device is an efficient form of drug delivery system which can provide high concentrations of drug in the tissues over an extended period of time to achieve antiproliferative therapeutic effect. The permanent stent implants pose the risk of a continuous interaction between the non-biodegradable polymer coating and intimal surface leading to physical irritation, endothelial dysfunction, hypersensitivity reactions, delayed healing and excess risk of late stent thrombosis. This review highlights the relationship between local drug delivery using the stent platform, release kinetics and local vascular toxicity.

Periadventitial local drug delivery to target 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.