Recruitment Of Vascular Cells Research Articles

Artificial Vasa‐Vasorum Serves as an On‐Site Regenerative Promoter of Cell‐Free Vascular Grafting

AbstractThe control paradigm of small vessel pathophysiology has changed to focus on the vascular out‐wall rather than the lumen‐intimal factors. As an emerging controller of the external wall, the microvasculature (“vasa vasorum”) provides interactional routes between the in‐and out‐sides of the vascular wall. Despite numerous approaches to developing small‐diameter vascular grafts, engineering artificial vasa vasorum (AVV) has not been projected as a multi‐functional solution to address long‐standing issues such as thrombotic and immune controls for wall regeneration. Here, the AVV is engineered using a microchannel network hydrogel after a multi‐study validation of implantation functions and then used to wrap the external wall of the cell‐free vessel post‐decellularization while preserving its mechanical properties. Upon inter‐positional and bypass grafting to rabbit arteries, the AVV graft facilitates the recruitment of vascular cells into the cell‐free wall by promoting invasion of angiogenic and vasculogenic cells through the microchannel‐mediated M2 polarization of macrophages. This function results in the efficient restoration of smooth muscle cells, and the revitalized vascular elasticity helps to maintain long‐term patency. The AVV, therefore, serves as an effective catalyst for vascular wall regeneration, offering a solution to clinically successful small‐diameter vascular grafting.

3D Printed Conductive Multiscale Nerve Guidance Conduit with Hierarchical Fibers for Peripheral Nerve Regeneration.

Nerve guidance conduits (NGCs) have become a promising alternative for peripheral nerve regeneration; however, the outcome of nerve regeneration and functional recovery is greatly affected by the physical, chemical, and electrical properties of NGCs. In this study, a conductive multiscale filled NGC (MF-NGC) consisting of electrospun poly(lactide-co-caprolactone) (PCL)/collagen nanofibers as the sheath, reduced graphene oxide /PCL microfibers as the backbone, and PCL microfibers as the internal structure for peripheral nerve regeneration is developed. The printed MF-NGCs presented good permeability, mechanical stability, and electrical conductivity, which further promoted the elongation and growth of Schwann cells and neurite outgrowth of PC12 neuronal cells. Animal studies using a rat sciatic nerve injury model reveal that the MF-NGCs promote neovascularization and M2 transition through the rapid recruitment of vascular cells and macrophages. Histological and functional assessments of the regenerated nerves confirm that the conductive MF-NGCs significantly enhance peripheral nerve regeneration, as indicated by improved axon myelination, muscle weight increase, and sciatic nerve function index. This study demonstrates the feasibility of using 3D-printed conductive MF-NGCs with hierarchically oriented fibers as functional conduits that can significantly enhance peripheral nerve regeneration.

Abstract P1142: Engineering Vascular Therapies With Angiogenic Factors For Cardiac Regeneration And Tissue Remodeling

The limited regenerative capacity of the adult human heart presents a critical need to stabilize and support injured heart muscle to mitigate the progression of heart failure. The effectiveness of remuscularization therapies using human induced pluripotent stem cell derived cardiomyocytes depends host mediated angiogenesis to direct the formation of stable, perfused vascular networks within the engineered cardiac implant. We hypothesize that potent combinations of growth factors will stimulate angiogenesis in the myocardium and increase vascular development in engineered cardiac tissue. In a fractional factorial experiment, we assessed the effect of ten growth factors, cytokines and enzymes: VEGF, bFGF, Shh, PDGF, IGF-1, EGF, TGF-β1, Ang-1, MCP-1 and MMP-9 on in vivo angiogenesis in a subcutaneous Matrigel plug assay in the rat. Five factors were highly potent by metrics of vessel density and vascular cell recruitment in explants and warranted further investigation. We then designed a two-level, fractional factorial experiment using a defined collagen-alginate gel to deliver high/low doses of these 5 factors subcutaneously to elucidate main effects and two-way interactions that regulate vessel development in vivo . After 7 days, Griffonia Simplicfolia lectin I was administered to label perfused vasculature then explants were removed and processed for immunohistochemistry. Our data show that 3 unique cocktails yielded a 10-fold increase in lumen density, a 3.3-fold increase in lumen size, and a 3.7-fold increase in endothelial cell recruitment relative to unloaded controls. Ongoing analyses will determine which angiogenic cocktail to deliver in a customizable biomaterial-based vascular therapy for applications in the heart. This novel therapy will be delivered with an engineered cardiac tissue onto the epicardium in a rat I/R MI model to quantify vascular remodeling in the implant and underlying host tissue and whole heart function over 4 weeks. In conclusion, we have identified five potent angiogenic factors for modulating revascularization responses and our ongoing work aims to understand the potential synergy between revascularization and remuscularization therapies for heart regeneration.

Unique Angiogenesis From Cardiac Arterioles During Pericardial Adhesion Formation.

ObjectivesThe molecular mechanisms underlying post-operative pericardial adhesions remain poorly understood. We aimed to unveil the temporal molecular and cellular mechanisms underlying tissue dynamics during adhesion formation, including inflammation, angiogenesis, and fibrosis.Methods and ResultsWe visualized cell-based tissue dynamics during pericardial adhesion using histological evaluations. To determine the molecular mechanism, RNA-seq was performed. Chemical inhibitors were administered to confirm the molecular mechanism underlying adhesion formation. A high degree of adhesion formation was observed during the stages in which collagen production was promoted. Histological analyses showed that arterioles excessively sprouted from pericardial tissues after the accumulation of neutrophils on the heart surface in mice as well as humans. The combination of RNA-seq and histological analyses revealed that hyperproliferative endothelial and smooth muscle cells with dedifferentiation appeared in cytokine-exposed sprouting vessels and adhesion tissue but not in quiescent vessels in the heart. SMAD2/3 and ERK activation was observed in sprouting vessels. The simultaneous abrogation of PI3K/ERK or TGF-β/MMP9 signaling significantly decreased angiogenic sprouting, followed by inhibition of adhesion formation. Depleting MMP9-positive neutrophils shortened mice survival and decreased angiogenic sprouting and fibrosis in the adhesion. Our data suggest that TGF-β/matrix metalloproteinase-dependent tissue remodeling and PI3K/ERK signaling activation might contribute to unique angiogenesis with dedifferentiation of vascular smooth muscle cells from the contractile to the synthetic phenotype for fibrosis in the pericardial cavity.ConclusionsOur findings provide new insights in developing prevention strategies for pericardial adhesions by targeting the recruitment of vascular cells from heart tissues.

The CXCL12/CXCR4 and VEGF165/Nrp1 Pathways Have Differential Effects on Pathological Neo-Angiogenesis and Vascular Remodeling in Hemophilic Arthropathy

Introduction: Joint hypervascularity is characteristic to hemophilic arthropathy (HA), which is a hallmark complication in patients with hemophilia. Angiogenesis in the hemophilic joint is triggered by bleeding and results in excessive vascular remodeling with enlarged irregularly shaped vessels that appear fragile, potentially causing re-bleeding. Therefore, targeting angiogenesis may offer novel treatment avenues in HA. Vascular endothelial growth factor A (VEGF-A) is an important angiogenic mediator implicated in the pathogenesis of HA, but a complete blockade may cause vascular instability with more bleeding, or inhibition of anti-angiogenic isoforms, thereby decreasing therapeutic efficacy. An alternative approach may be to target the co-receptor Neuropilin 1 (Nrp1) that facilitates binding of the pro-angiogenic isoform VEGF165 to its signaling receptor, VEGFR2. Here, we determine whether blocking the binding of VEGF165 to Nrp1 can curb the pathological vascular remodeling associated with hemophilic joint bleeding.Methods and results: Joint bleeding was induced by subpatellar needle puncture in FVIII-/- mice, resulting in pronounced intra- and peri-articular bleeding, evidenced by a drop in hematocrit from ~45% to 28 ± 10% 2 days after injury. The following antibody treatments were initiated 2 days after injury and were administered at 5 mg/kg, twice weekly for 4 weeks: B20-4 targeting murine VEGF-A, and YW107.4.87 blocking the VEGF165 binding site on Nrp1. The CXCR4 antagonist, AMD3100 (300 µg/day by subcutaneous osmotic pump) was included as positive control as it corrects hypervascularity induced by hemophilic joint bleeding (Wyseure et al . ISTH 2017).Four weeks after injury blood flow in the joint, measured by ultrasound-Power Doppler (PD), was increased 2.8-fold in injured vs uninjured FVIII-/- mice (p<0.001; n=13). Anti-VEGF treatment resulted in a similar 3.2-fold increase in PD signal (n=8), indicating that total inhibition of VEGF had no effect on the aberrant blood flow. Inhibition of Nrp1 had a partial effect (1.9-fold increase over baseline; p=0.16 vs no treatment; n=7), whereas inhibition of CXCL12-mediated vascular cell recruitment by the CXCR4 antagonist significantly blunted aberrant PD signals (p<0.05 vs no treatment; n=10). On histology, the total vessel count after anti-Nrp1 treatment was similar to no treatment and significantly greater than baseline (86 anti-Nrp1 vs 80 no treatment vs 42 baseline; p<0.01). Similarly, anti-Nrp1 treatment had no effect on the number of abnormally enlarged vessels (with a diameter ≥ 20 µm) compared to no treatment (15 anti-Nrp1 vs 13 no treatment vs 3 baseline; p<0.01 vs baseline). In contrast, with CXCR4 antagonist treatment both the total vessel count (64; p=0.3 vs baseline) and the number of abnormally enlarged vessels (7; p=0.1 vs baseline) remained low. However, anti-Nrp1 treatment did prevent the 2.5-fold increased perivascular expression of smooth muscle cell actin (αSMA; p<0.01) that typically accompanies the abnormally enlarged vessels in injured FVIII-/- mice. Thus, inhibition of Nrp1 lowered αSMA expression after hemophilic bleeding, similar to baseline and CXCR4 antagonist treatment, although it had no effects on vessel number and enlargement. This suggests that anti-Nrp1 treatment prevents the maturation during vascular remodeling in HA, potentially leaving the vessels destabilized and prone to vascular permeability. Towards that end, staining with Prussian Blue demonstrated increased hemosiderin deposits in anti-Nrp1 treated mice, similar to untreated injured FVIII-/- mice, whereas no signs of macroscopic joint bleeding or hemosiderin deposits were observed after treatment with the CXCR4 antagonist.Conclusions: Abrogating the VEGF165-Nrp1 interaction was not sufficient to prevent neo-angiogenesis and vessel lumen expansion in a murine hemophilic joint injury model. However, inhibition of Nrp1 did reduce perivascular remodeling that may allow regression of the aberrant vasculature over time, but also may promote further vessel instability and additional hemorrhaging. Thus, inhibition of the CXCL12/CXCR4 pathway affects neo-angiogenesis, whereas inhibition of the VEGF165/Nrp1 pathway predominantly affects perivascular maturation, but not neo-angiogenesis. These findings provide novel insights on the potential benefits and pitfalls of anti-angiogenic treatments in HA. Disclosuresvon Drygalski:Hematherix LLC: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novo Nordisk: Honoraria; CSL Behring: Honoraria; Bioverativ: Honoraria; Bayer: Honoraria; Shire: Honoraria. Mosnier:Hematherix LLC: Membership on an entity's Board of Directors or advisory committees.

Effects of recipient age, heparin release and allogeneic bone marrow-derived stromal cells on vascular graft remodeling

Small-caliber vascular grafts are used in a wide range of clinical conditions. However, there remains a substantial unfulfilled need for readily-available, synthetic vascular grafts with high long-term patency rate. To fulfill the translational goal for bioengineered vascular grafts, important considerations for the pre-clinical evaluation include the graft design, cell incorporation and selection of an animal model. To assess the three factors, we used vascular grafts consisting of core/shell-structured microfibers of polycaprolactone/gelatin with a thin polycaprolactone overlay. The respective influences of the heparin release mode, animal age, and allogeneic bone marrow-derived stromal cells (MSCs) seeded in the lumen on the graft remodeling were assessed after four-and-half-month implantation on an interposition graft of abdominal aorta model. Except two rats dying from graft-unrelated issues, all other rats (18 out of 20) showed good graft patency upon explantation. The cell phenotype, matrix content and structure in the neotissues around the graft, as well as the flow perfusion through the graft were examined. More grafts in the aged rats showed local narrowing and flow incongruence than the other grafts in young adult rats. Compared to acellular grafts, cellular grafts showed efficient recruitment of vascular cells to form more organized structures with elastin in the vascular wall. Endothelialization and α−smooth muscle actin-positive cells were shown in all four types of vascular grafts. This study revealed the significant effects of MSC and recipient age but not heparin release pattern on graft remodeling. Statement of significanceThe vascular graft is a mainstream of surgical intervention to treat vascular diseases. Currently, vascular grafts, particularly small-diameter ones, still show high failure rates. This study has evaluated the respective impacts of heparin release pattern, allogeneic bone marrow-derived stromal cell seeding, and recipient age on the long-term remodeling of vascular grafts. There is a dearth of literature which considers the recipient age as an influencing factor for vascular grafting. However, adults particularly elderly constitute the majority of vascular graft recipients in the “real” clinical environment. While juvenile animals were widely used for graft evaluations, this study involved adult animals. The study outcomes provided important implications regarding graft designs and evaluation approaches.

A novel role of FKN/CX3CR1 in promoting osteogenic transformation of VSMCs and atherosclerotic calcification

Fractalkine (FKN) and its specific receptor CX3CR1 play a critical role in the pathogenesis of atherosclerosis including recruitment of vascular cells and the development of inflammation. However, its contribution to regulating the development of atherosclerotic calcification has not been well documented. Osteogenic transformation of vascular smooth muscle cells (VSMCs) is critical in the development of calcification in atherosclerotic lesions. In this study, for the first time, we evaluated the effect of FKN/CX3CR1 on the progression of VSMCs calcification and defined molecular signaling that is operative in the FKN/CX3CR1-induced osteogenic transformation of VSMCs. We found that high-fat diet induced atherosclerotic calcification in vivo was markedly inhibited in the Apolipoprotein E (ApoE) and CX3CR1 deficient (ApoE−/−/CX3CR1−/−) mice compared with their control littermates. FKN and CX3CR1 were both expressed in VSMCs and up-regulated by oxidized low-density lipoprotein (ox-LDL). FKN/CX3CR1 promoted the expression of osteogenic markers, including osteopontin (OPN), bone morphogenetic protein (BMP)-2 and alkaline phosphatase (ALP) and decreased VSMCs markers, including smooth muscle (SM) α-actin and SM22-α in a dose-dependent manner. The essential role of FKN/CX3CR1 in VSMCs calcification was further confirmed by lentivirus-mediated knockdown or overexpression of CX3CR1 blocked or accelerated osteogenic transformation of VSMCs. This response was associated with reciprocal up- and down-regulation of osteogenic factor, runt-related transcription factor 2 (RUNX2), transcription factors in osteoclast differentiation, receptor activator of nuclear factor-κB (RANK), RANK ligand (RNAKL) and osteoprotegerin (OPG), respectively. Inhibition of FKN/CX3CR1-activated Jak2/Stat3 signaling by the Jak/Stat inhibitor AG490 blocked osteogenic transformation of VSMCs and RUNX2 induction concurrently. Taken together, our data uncovered novel roles of FKN/CX3CR1 in promoting VSMC osteogenic transformation and atherosclerotic calcification by activating RUNX2 through Jak2/Stat3 signaling pathway and suppressing OPG. Our findings suggest that targeting FKN/CX3CR1 may provide new strategies for the prevention and treatment of atherosclerotic calcification.

Angiogenic peptide nanofibers repair cardiac tissue defect after myocardial infarction.

We present a synthetic bioactive peptide nanofiber system can enhance cardiac function and enhance cardiovascular regeneration after myocardial infarction (MI) without the addition of growth factors, stem cells or other biologically derived molecules. Current state of the art in cardiac repair after MI utilize at least one of the above mentioned biologically derived molecules, thus our approach is ground-breaking for cardiovascular therapy after MI. In this work, we showed that synthetic glycosaminoglycan (GAG) mimetic peptide nanofiber scaffolds induce neovascularization and cardiomyocyte differentiation for the regeneration of cardiovascular tissue after myocardial infarction in a rat infarct model. When the peptide nanofiber gels were injected in infarct site at rodent myocardial infarct model, recruitment of vascular cells was observed, neovascularization was significantly induced and cardiac performance was improved. These results demonstrate the potential of future clinical applications of these bioactive peptide nanofibers as a promising strategy for cardiovascular repair.

High Aldehyde Dehydrogenase Activity Identifies a Subset of Human Mesenchymal Stromal Cells with Vascular Regenerative Potential.

During culture expansion, multipotent mesenchymal stromal cells (MSCs) differentially express aldehyde dehydrogenase (ALDH), an intracellular detoxification enzyme that protects long-lived cells against oxidative stress. Thus, MSC selection based on ALDH-activity may be used to reduce heterogeneity and distinguish MSC subsets with improved regenerative potency. After expansion of human bone marrow-derived MSCs, cell progeny was purified based on low versus high ALDH-activity (ALDHhi ) by fluorescence-activated cell sorting, and each subset was compared for multipotent stromal and provascular regenerative functions. Both ALDHl ° and ALDHhi MSC subsets demonstrated similar expression of stromal cell (>95% CD73+ , CD90+ , CD105+ ) and pericyte (>95% CD146+ ) surface markers and showed multipotent differentiation into bone, cartilage, and adipose cells in vitro. Conditioned media (CDM) generated by ALDHhi MSCs demonstrated a potent proliferative and prosurvival effect on human microvascular endothelial cells (HMVECs) under serum-free conditions and augmented HMVEC tube-forming capacity in growth factor-reduced matrices. After subcutaneous transplantation within directed in vivo angiogenesis assay implants into immunodeficient mice, ALDHhi MSC or CDM produced by ALDHhi MSC significantly augmented murine vascular cell recruitment and perfused vessel infiltration compared with ALDHl ° MSC. Although both subsets demonstrated strikingly similar mRNA expression patterns, quantitative proteomic analyses performed on subset-specific CDM revealed the ALDHhi MSC subset uniquely secreted multiple proangiogenic cytokines (vascular endothelial growth factor beta, platelet derived growth factor alpha, and angiogenin) and actively produced multiple factors with chemoattractant (transforming growth factor-β, C-X-C motif chemokine ligand 1, 2, and 3 (GRO), C-C motif chemokine ligand 5 (RANTES), monocyte chemotactic protein 1 (MCP-1), interleukin [IL]-6, IL-8) and matrix-modifying functions (tissue inhibitor of metalloprotinase 1 & 2 (TIMP1/2)). Collectively, MSCs selected for ALDHhi demonstrated enhanced proangiogenic secretory functions and represent a purified MSC subset amenable for vascular regenerative applications. Stem Cells 2017;35:1542-1553.

Abstract 1525: Regulation of bone marrow angiogenesis by CXCL12 in the leukemia tumor microenvironment

Abstract While it is well established that angiogenesis is essential for the progression of solid tumors, its role in hematological tumors is more recently becoming fully appreciated. In the current study we have investigated the potential role of leukemic cells in regulating local angiogenesis as well as the modulation of tumor cell CXCL12 expression subsequent to interaction with bone marrow derived osteoblasts as one mechanism by which local vascular rich niches may be created. Human REH acute lymphoblastic leukemia (ALL; ATCC #CRL-8286) increased vessel density when placed on the chorioallantoic membrane (CAM) assay. Conditioned media from these same tumor cells increased human brain microvessel endothelial cell (HBMEC) motility and tube formation suggesting leukemia cell influence on surrounding vasculature. Strikingly, while REH cells express negligible CXCL12 at baseline, the chemokine is consistently induced to easily detectable levels upon co-culture with human osteoblasts indicating one mechanism by which tumor cells within the bone marrow microenvironment may be poised to enhance vascular cell recruitment even more robustly than leukemic cells alone. Preliminary evaluation of primary, patient-derived ALL leukophoresis samples demonstrated a comparable increase in tumor cell CXCL12 indicating this modulation is not limited to an established tumor cell line. Increased expression of CXCL12 by REH leukemic cells was consistent with enhanced chemotaxis of HUVECs toward the co-culture of tumor and osteoblasts when compared to either cell type alone. The inclusion of 5-Aza-deoxycytidine (Aza-C) to REH cells alone resulted in expression of CXCL12 in the absence of osteoblast co-culture, suggesting methylation may play a regulatory role in the suppression of this chemokine. As a site in which metastatic disease is often refractory to standard therapy, in addition to the anatomical niche in which hematopoietic malignancies initiate and most frequently relapse, regulation of local angiogenesis in the bone marrow microenvironment requires further investigation. Our preliminary observations suggest CXCL12 may play an important role in regulating leukemic cell niche angiogenesis, and targeting it could potentially represent a novel application of antagonists currently in clinical trials in an effort to treat refractory leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1525. doi:1538-7445.AM2012-1525

Vascular endothelial growth factor can signal through platelet-derived growth factor receptors

Vascular endothelial growth factor (VEGF-A) is a crucial stimulator of vascular cell migration and proliferation. Using bone marrow–derived human adult mesenchymal stem cells (MSCs) that did not express VEGF receptors, we provide evidence that VEGF-A can stimulate platelet-derived growth factor receptors (PDGFRs), thereby regulating MSC migration and proliferation. VEGF-A binds to both PDGFRα and PDGFRβ and induces tyrosine phosphorylation that, when inhibited, results in attenuation of VEGF-A–induced MSC migration and proliferation. This mechanism was also shown to mediate human dermal fibroblast (HDF) migration. VEGF-A/PDGFR signaling has the potential to regulate vascular cell recruitment and proliferation during tissue regeneration and disease.

Atherosclerosis 2005

Atherosclerosis is an inflammatory process that selectively affects arteries and is highly prevalent in both women and men. Thrombo-occlusive complications of atherosclerosis, including stroke and myocardial infarction, are major causes of morbidity and mortality. Senescence of the arterial tree is a biological process that follows a natural course that can be accelerated by the combined injury of multiple risk factors. A repair capacity that is intrinsic to the organism can counteract the natural time- and risk factor– dependent obsolescence of arteries. The failure of this repair process is intimately linked to atherosclerotic inflammation and lesion formation. Recruitment and targeting of bone marrow–derived progenitor vascular cells, and probably vascular progenitors originating in other tissues, that have an intrinsic capacity for repair of the vascular wall represent a promising area for research and development. This review focuses on recent discoveries relevant to vascular progenitor cells and others that are likely to influence atherosclerosis research. It highlights the exciting recent findings that demonstrate the vital role of vascular progenitor cells in the homeostasis of the vessel wall and the mitigation of atherosclerosis. In the context of atherosclerosis, this review also discusses the relevance of this paradigm to pharmacological treatment of atherosclerosis and the process of aging.

Platelets and Chemokines in Atherosclerosis

It becomes increasingly evident that blood platelets do not only exert important functions in hemostasis and thrombus formation but are also involved in atherosclerotic vascular disease. A major portion of the underlying mechanisms is related to an intricate functional interaction of platelets with chemokines, which have also been implicated in atherogenesis and neointima formation: (1) Platelets can induce the secretion of chemokines in different cells of the vascular wall; (2) In combination with primary agonists, certain chemokines can potentiate platelet aggregation and adhesion; (3) Activated platelets can release and deposit chemokines and precursors on vascular cell surfaces, which trigger atherogenic recruitment of vascular cells or modulate crucial processes such as angiogenesis and lipoprotein metabolism; (4) Surface-adherent platelets can bind and present vascular cell-derived chemokines to trigger arrest of circulating mononuclear cells. The close linkage between platelets and chemokines as culprits in the pathogenesis of vascular diseases may provide a valuable target for selective interventions.

Injectable Self-Assembling Peptide Nanofibers Create Intramyocardial Microenvironments for Endothelial Cells

Promoting survival of transplanted cells or endogenous precursors is an important goal. We hypothesized that a novel approach to promote vascularization would be to create injectable microenvironments within the myocardium that recruit endothelial cells and promote their survival and organization. In this study we demonstrate that self-assembling peptides can be injected and that the resulting nanofiber microenvironments are readily detectable within the myocardium. Furthermore, the self-assembling peptide nanofiber microenvironments recruit progenitor cells that express endothelial markers, as determined by staining with isolectin and for the endothelial-specific protein platelet-endothelial cell adhesion molecule-1. Vascular smooth muscle cells are recruited to the microenvironment and appear to form functional vascular structures. After the endothelial cell population, cells that express alpha-sarcomeric actin and the transcription factor Nkx2.5 infiltrate the peptide microenvironment. When exogenous donor green fluorescent protein-positive neonatal cardiomyocytes were injected with the self-assembling peptides, transplanted cardiomyocytes in the peptide microenvironment survived and also augmented endogenous cell recruitment. These experiments demonstrate that self-assembling peptides can create nanofiber microenvironments in the myocardium and that these microenvironments promote vascular cell recruitment. Because these peptide nanofibers may be modified in a variety of ways, this approach may enable injectable tissue regeneration strategies.

A potent activator of PPARα and γ reduces the vascular cell recruitment and inhibits the intimal thickning in hypercholesterolemic rabbits

Peroxisome proliferator-activated receptors (PPARs) regulate the vascular cell functions as well as systemic lipid and glucose metabolism. Here, we studied the effect of TAK-559, a newly developed potent activator both for PPARα and γ, on the vascular cell recruitment. TNF-α - or interleukin-1β (IL-1β)-induced THP-1 cell attachment to cultured endothelial cells was significantly reduced in the presence of 10 μM TAK-559 ( P < 0.05). The secretion of monocyte chemoattractant protein-1 (MCP-1) from endothelial cells is reduced by 36% in the presence of 10 μM TAK-559, accompanied with the decreased mRNA expression in the cells. The proliferation and migration of cultured smooth muscle cells (SMCs) were significantly decreased in the presence of TAK-559 ( P < 0.05). TAK-559-treated hypercholesterolemic rabbits showed the significant reduction of intimal thickning after balloon catheterization by 51% compared with control ( P < 0.05), although the plasma lipid and glucose level was not changed between them. The numbers of macrophage and SMCs were decreased to 34% and 49% in the hyperplastic intima of arteries from TAK-559-treated rabbits compared to those from control, respectively. These results suggest that the PPARα and γ activator inhibits the recruitment of macrophages and SMCs in intima, possibly leading to the reduction of intimal hyperplasia in hypercholesterolemia.