Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic potential of low-molecular-weight (LMW) fucoidan, a sulfated polysaccharide extracted from brown seaweed devoid of direct antithrombin effect, was investigated in vitro and in a model of critical hindlimb ischemia in rat. In vitro results showed that LMW fucoidan enhanced fibroblast growth factor (FGF)-2-induced [(3)H]thymidine incorporation in cultured rat smooth muscle cells. Intravenous injection in rats of LMW fucoidan significantly increased the stromal-derived factor (SDF)-1 level from 1.2 +/- 0.1 to 6.5 +/- 0.35 ng/ml in plasma. The therapeutic effect of LMW fucoidan (5 mg/kg/day), FGF-2 (1 micro g/kg/day), and LMW fucoidan combined with FGF-2 was assessed 14 days after induction of ischemia by 1) clinical evaluation of claudication, 2) tissue blood flow analysis, 3) histoenzymology of muscle metabolic activity, and 4) quantification of capillary density. Both LMW fucoidan and FGF-2 similarly improved residual muscle blood flow (62.5 +/- 6.5 and 64.5 +/- 4.5%, respectively) compared with the control group (42 +/- 3.5%, p < 0.0001). The combination of FGF-2 and LMW fucoidan showed further significant improvement in tissue blood flow (90.5 +/- 3%, p < 0.0001). These results were confirmed by phosphorylase activity, showing muscle regeneration in rats treated with the combination of FGF-2 and LMW fucoidan. Capillary density count increased from 9.6 +/- 0.7 capillaries/muscle section in untreated ischemic controls to 14.3 +/- 0.9 with LMW fucoidan, 14.5 +/- 0.9 with FGF-2, and 19.1 +/- 0.9 in combination (p < 0.001). Thus, LMW fucoidan potentiates FGF-2 activity, mobilizes SDF-1, and facilitates angiogenesis in a rat model. This natural compound could be of interest as an alternative for conventional treatment in critical ischemia.
 ...
PMID:Low-molecular-weight fucoidan promotes therapeutic revascularization in a rat model of critical hindlimb ischemia. 1264 49

Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, "side population" cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically regulated. Stimulatory (eg, statins and exercise) or inhibitory factors (risk factors for coronary artery disease) modulate progenitor cell levels and, thereby, affect the vascular repair capacity. Moreover, recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events including adhesion and migration (eg, by integrins), chemoattraction (eg, by SDF-1/CXCR4), and finally the differentiation to endothelial cells. This review summarizes the mechanisms regulating endothelial progenitor cell-mediated neovascularization and reendothelialization.
 ...
PMID:Endothelial progenitor cells: characterization and role in vascular biology. 1532 44

Stem cell therapies, such as bone marrow transplantation, are a promising strategy for the treatment of stroke. Bone marrow-derived stem cells (BMSCs) including both hematopoietic and mesenchymal stem cells (HSCs and MSCs) can exhibit tremendous cellular differentiation in numerous organs. BMSCs may also promote structural and functional repair in several organs such as the heart, liver, brain, and skeletal muscle via stem cell plasticity. Interestingly, ischemia is known to induce mobilization of BMSCs in both animal models and humans. The tissue injury is "sensed" by the stem cells and they migrate to the site of damage and undergo differentiation. The plasticity, differentiation, and migratory functions of BMSCs in a given tissue are dependent on the specific signals present in the local micro-environment of the damaged tissue. Therefore, the ischemic micro-environment has critical patho-biological functions that are essential for the seeding, expansion, survival, renewal, growth and differentiation of BMSCs in damaged brain remodeling. Recent studies have identified the specific molecular signals, such as SDF-1/CXCR4, required for the interaction of BMSCs and damaged host tissues. Understanding the exact molecular basis of stem cell plasticity in relation to local ischemic signals could offer new insights to permit better management of stroke and other ischemic disorders. The aim of this review is to summarize recent studies into how BMSCs reach, recognize, and function in cerebral ischemic tissues, with particular regard to phenotypical reprogramming of stem cells, or "stem cell plasticity".
 ...
PMID:Homing genes, cell therapy and stroke. 1614 79

Circulating endothelial progenitor cells (EPC) are incorporated into newly formed capillaries, enhance neovascularization after hind limb ischemia and improve cardiac function after ischemic injury. Incorporated progenitor cells may also promote neovascularization and cardiac regeneration by releasing factors, which act in a paracrine manner to support local angiogenesis and mobilize tissue residing progenitor cells. Therefore, we analyzed the expression profile of cytokines in human peripheral blood-derived EPC as opposed to human umbilical vein endothelial cells (HUVEC), human microvascular endothelial cells (HMVEC), and CD14(+) monocytes by microarray technology. A gene tree analysis revealed a distinct expression pattern of angiogenic growth factors in EPC, mature endothelial cells, and CD14(+) monocytes. VEGF-A, VEGF-B, SDF-1, and IGF-1 mRNA levels were higher in EPC as compared to HUVEC or HMVEC. The enhanced mRNA expression was paralleled by a significant release of VEGF, SDF-1, and IGF-1 protein into the cell culture supernatant of EPC. Moreover, immunohistological analysis of ischemic limbs from nude rats revealed that VEGF is also released from recruited human EPC in vivo. As a functional consequence, conditioned medium of EPC induced a strong migratory response of mature endothelial cells, which was significantly inhibited by VEGF and SDF-1 neutralizing antibodies. Finally, conditioned medium of EPC significantly stimulated the migration of cardiac resident c-kit(+) progenitor cells in vitro. Taken together, EPC exhibit a high expression of angiogenic growth factors, which enhanced migration of mature endothelial cells and tissue resident cardiac progenitor cells. In addition to the physical contribution of EPC to newly formed vessels, the enhanced expression of cytokines may be a supportive mechanism to improve blood vessel formation and cardiac regeneration after cell therapy.
 ...
PMID:Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. 1632 97

Our goal was to identify functionally important subpopulations within the heterogenous group of endothelial progenitor cells (EPC). Fluorescence-activated cell sorter analysis of CD133+ progenitor cells revealed the presence of CD34+ and CD34- subpopulations. CD34-/133+ progenitors differentiate into CD34+/133+ EPC, adhere more potently than these in response to SDF-1, and rapidly home to sites of limb ischemia in human volunteers. In human coronary atherectomy samples, fewer CD34-/133+ than CD34+/133+ EPC are present in stable plaques, whereas cell numbers increase with a reversion of the ratio in unstable lesions. In CD34-/133+ EPC-injected nude mice, more transplanted cells coexpressing endothelial markers home to carotid artery lesion endothelium than in CD34+/133+-injected mice. In the former, lesions were smaller and reendothelialization higher than in the latter. We identified a new CD34-/133+ EPC subpopulation, which is apparently a precursor of "classical" CD34+/133+ EPC, and functionally more potent than these with respect to homing and vascular repair.
 ...
PMID:CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. 1643 88

When neovascularization is triggered in ischemic tissues, angiogenesis but also (postnatal) vasculogenesis is induced, the latter requiring the mobilization of endothelial progenitor cells (EPC) from the bone marrow. Caveolin, the structural protein of caveolae, was recently reported to directly influence the angiogenic process through the regulation of the vascular endothelial growth factor (VEGF)/nitric oxide pathway. In this study, using caveolin-1 null mice (Cav(-/-)), we examined whether caveolin was also involved in the EPC recruitment in a model of ischemic hindlimb. Intravenous infusion of Sca-1(+) Lin(-) progenitor cells, but not bone marrow transplantation, rescued the defective neovascularization in Cav(-/-) mice, suggesting a defect in progenitor mobilization. The adhesion of Cav(-/-) EPC to bone marrow stromal cells indeed appeared to be resistant to the otherwise mobilizing SDF-1 (Stromal cell-Derived Factor-1) exposure because of a defect in the internalization of the SDF-1 cognate receptor CXCR4. Symmetrically, the attachment of Cav(-/-) EPC to SDF-1-presenting endothelial cells was significantly increased. Finally, EPC transduction with caveolin small interfering RNA reproduced this advantage in vitro and, importantly, led to a more extensive rescue of the ischemic hindlimb after intravenous infusion (versus sham-transfected EPC). These results underline the critical role of caveolin in ensuring the caveolae-mediated endocytosis of CXCR4, regulating both the SDF-1-mediated mobilization and peripheral homing of progenitor cells in response to ischemia. In particular, a transient reduction in caveolin expression was shown to therapeutically increase the engraftment of progenitor cells.
 ...
PMID:Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven postischemic vasculogenesis. 1660 Dec 28

In the article we present the latest knowledge about angiogenesis. We have divided the paper into three main parts, in which the involvement of the extracellular matrix, cells, and cytokines/growth factors in the growth of new blood vessels is described. In brief, the extracellular compartment plays a crucial role in the formation of new vasculature. Degradation of matrix is a very important and precisely controlled process performed mostly by a family of proteins called matrix metallproteinases (MMPs). The extracellular compartment, through the special transmembrane proteins integrins, transmit a wide variety of signals into the cells and thus influence such cell behavior as proliferation, invasion, shape, migration, and maturation. Many products of matrix degradation are potent (mostly negative) regulators of angiogenesis; this self-limiting system prevents excessive proteolysis of the matrix components. The cells involved in the process are endothelial progenitor cells (EPCs), which are derived from bone marrow. The major surface antigens of the cells are CD34+, CD133+, and VEGFR2+. It has been demonstrated that EPCs are responsible for maintaining the functional integrity of endothelium. The number of EPCs in peripheral blood samples inversely correlates with cardiovascular risk factors. In the last section of the article the role of cytokines/growth factors is described. VEGF, as a key regulator of the initial steps of angiogenesis, controls the mobilization and incorporation of EPCs into the site of ischemia. The most important cytokine that facilitates the mobilization of EPCs from bone marrow is SDF-1, which is the strongest chemoattractant for EPCs. Ang-1, on the other hand, controls new blood vessel maturation and stabilization.
 ...
PMID:[Molecular basics of angiogenesis]. 1692 41

Thrombopoietic cells may differentially promote or inhibit tissue vascularization by releasing both pro- and antiangiogenic factors. However, the molecular determinants controlling the angiogenic phenotype of thrombopoietic cells remain unknown. Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch. TSPs inhibited thrombopoiesis, diminished bone marrow microvascular reconstruction following myelosuppression, and limited the extent of revascularization in a model of hind limb ischemia. We demonstrate that thrombopoietic recovery following myelosuppression was significantly enhanced in mice deficient in both TSP1 and TSP2 (TSP-DKO mice) in comparison with WT mice. Megakaryocyte and platelet levels in TSP-DKO mice were rapidly restored, thereby accelerating revascularization of myelosuppressed bone marrow and ischemic hind limbs. In addition, thrombopoietic cells derived from TSP-DKO mice were more effective in supporting neoangiogenesis in Matrigel plugs. The proangiogenic activity of TSP-DKO thrombopoietic cells was mediated through activation of MMP-9 and enhanced release of stromal cell-derived factor 1. Thus, TSP-deficient thrombopoietic cells function as proangiogenic agents, accelerating hemangiogenesis within the marrow and revascularization of ischemic hind limbs. As such, interference with the release of cellular stores of TSPs may be clinically effective in augmenting neoangiogenesis.
 ...
PMID:Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. 1714 27

Previous in vitro studies have revealed that oxidized low density lipoprotein (OxLDL) has negative effects on the proliferation and activity of endothelial progenitor cells (EPCs). Here, we evaluated the effect of OxLDL on the therapeutic potential of EPCs in ischemia-induced neovascularization. EPCs derived from mobilized human peripheral blood mononuclear cells were cultured without or with OxLDL before transplantation. Hindlimb ischemia models were surgically induced in athymic nude mice, which then received an intracardiac injection of 3 x 10(5) EPCs. By laser Doppler perfusion image and ischemia damage score, we found that blood perfusion and ischemia damage were less well recovered in the OxLDL-treated EPC transplantation group than in controls. Histological examination showed fewer transplanted EPCs and lower capillary density in ischemic tissue. Local delivery of Stromal cell-derived factor (SDF-1) restored this defect and improved blood perfusion by recruiting OxLDL-treated EPCs to the ischemic area and increasing host capillary density. These results provide for the first time direct evidence that OxLDL impaired the therapeutic potential of EPCs in ischemia-induced neovascularization through an inhibitory effect on the migration, adhesion, and incorporation of EPCs into vasculature and/or entrapment in the perivascular region in vivo. A therapeutic strategy based on SDF-1 administration ameliorated such defects and improved postischemic neovascularization.
 ...
PMID:Impaired therapeutic vasculogenesis by transplantation of OxLDL-treated endothelial progenitor cells. 1718 50

Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4(+) BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4(+)VEGFR1(+) hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.
 ...
PMID:The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. 1756 Jan 69


1 2 3 4 5 6 7 8 Next >>