Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury

Iwakura, Atsushi; Luedemann, Corinne; Shastry, Shubha; Hanley, Allison; Kearney, Marianne; Aikawa, Ryuichi; Isner, Jeffrey M.; Asahara, Takayuki; Losordo, Douglas W.

doi:10.1161/01.cir.0000106906.56972.83

Cited by 392 publications

(320 citation statements)

References 37 publications

Supporting

Mentioning

305

Contrasting

Unclassified

Order By: Relevance

“…Secondly, our results pertain only to men. Considering estrogen has been shown to affect both the number and function of circulating cells associated with vascular repair (21,22), the onset and magnitude of the age-related decline in CD31 ϩ T-cell number and migratory capacity observed in men may differ in women. Thus the results of this study should be viewed in this context and any extrapolation to women done with caution.…”

Section: Discussionmentioning

confidence: 99%

Human aging and CD31⁺T-cell number, migration, apoptotic susceptibility, and telomere length

Kushner

Weil

MacEneaney

et al. 2010

Journal of Applied Physiology

View full text Add to dashboard Cite

Kushner EJ, Weil BR, MacEneaney OJ, Morgan RG, Mestek ML, Van Guilder GP, Diehl KJ, Stauffer BL, DeSouza CA. Human aging and CD31 ϩ T-cell number, migration, apoptotic susceptibility, and telomere length. J Appl Physiol 109: 1756 -1761. First published September 23, 2010 doi:10.1152/japplphysiol.00601.2010.-CD31 ϩ T cells, or so-called "angiogenic T cells," have been shown to demonstrate vasculoprotective and neovasculogenic qualities. The influence of age on CD31 ϩ T-cell number and function is unclear. We tested the hypothesis that circulating CD31 ϩ T-cell number and migratory capacity are reduced, apoptotic susceptibility is heightened, and telomere length is shortened with advancing age in adult humans. Thirtysix healthy, sedentary men were studied: 12 young (25 Ϯ 1 yr), 12 middle aged (46 Ϯ 1 yr), and 12 older (64 Ϯ 2 yr). CD31 ϩ T cells were isolated from peripheral blood samples by magnetic-activated cell sorting. The number of circulating CD31 ϩ T cells (fluorescenceactivated cell sorting analysis) was lower (P Ͻ 0.01) in older (24% of CD3 ϩ cells) compared with middle-aged (38% of CD3 ϩ cells) and young (40% of CD3 ϩ cells) men. Migration (Boyden chamber) to both VEGF and stromal cell-derived factor-1␣ was markedly blunted (P Ͻ 0.05) in cells harvested from middle-aged [306.1 Ϯ 45 and 305.6 Ϯ 46 arbitrary units (AU), respectively] and older (231 Ϯ 65 and 235 Ϯ 62 AU, respectively) compared with young (525 Ϯ 60 and 570 Ϯ 62 AU, respectively) men. CD31 ϩ T cells from middle-aged and older men demonstrated greater apoptotic susceptibility, as staurosporine-stimulated intracellular caspase-3 activation was ϳ40% higher (P Ͻ 0.05) than young. There was a progressive age-related decline in CD31 ϩ T-cell telomere length (young: 10,706 Ϯ 220 bp; middle-aged: 10,179 Ϯ 251 bp; and older: 9,324 Ϯ 192 bp). Numerical and functional impairments in this unique T-cell subpopulation may contribute to diminished angiogenic potential and greater cardiovascular risk with advancing age. age; apoptosis; vascular CD31 OR PLATELET/ENDOTHELIAL cell adhesion molecule (PECAM) is a glycoprotein present on the surface of immune cells including platelets, monocytes, and granulocytes (4, 38). The CD31 receptor globulin is composed of six extracellular immunoglobulin repeats followed by a transmembrane domain and two cytosolic immunoreceptor tyrosine inhibitory motifs that carry a diverse array of signaling consequences known to be involved in cell phenotype determination, gene expression, and cell cycle (29,30,36). The unique structural homology of CD31's extracellular region is responsible for facilitating numerous heterophilic and homophilic binding interactions between differing vascular tissues (10, 16). For example, CD31 is highly expressed in the border junctions of endothelial cells where it plays a role in endothelial cell motility and regulating leukocyte transendothelial migration (31). In CD31 knockout mice, endothelial cell motility and filopodia formation as well as neovascularization are markedly impaired (5).Recently,...

show abstract

Section: Discussionmentioning

confidence: 99%

Human aging and CD31⁺T-cell number, migration, apoptotic susceptibility, and telomere length

Kushner

Weil

MacEneaney

et al. 2010

Journal of Applied Physiology

View full text Add to dashboard Cite

show abstract

“…Vascular endothelial injury is an important risk factor for atherosclerosis and restenosis. To study the repair and remodeling processes, in previous studies, endothelial injury has been induced mechanically by (i) different diameters of angioplasty guide wire, [20][21][22][23] (ii) spring wire, 22 (iii) ligating the arteries using 9-0 nylon sutures, 23 (iv) placing a cuff, 24 (v) balloon distension, (vi) air desiccation and (vii) treatment with chemicals that selectively remove endothelial cells. However, shortcomings in most of these methods are unavoidable.…”

Section: Discussionmentioning

confidence: 99%

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Mohan

Reddick

Musi

et al. 2008

Laboratory Investigation

108

119

View full text Add to dashboard Cite

Functional consequences of impaired endothelial nitric oxide synthase (eNOS) activity causing organ-specific abnormalities on a diabetic setting are not completely understood. In this study, we extensively characterized a diabetic mouse model (lepr db/db ) in which eNOS expression is genetically disrupted (eNOS À/À ). The eNOS À/À / lepr db/db double-knockout (DKO) mice developed obesity, hyperglycemia, hyperinsulinemia and hypertension. Analysis of tissues from DKO mice showed large islets in the pancreas and fat droplets in hepatocytes. Interestingly, the aorta was normal and atherogenic lesions were not observed. Abnormalities in the aorta including poor re-endothelialization and increased medial wall thickness were evident only in response to deliberate injury. In contrast, significant glomerular capillary damage in the kidney was identified, with DKO mice demonstrating a robust diabetic nephropathy similar to human disease. The vascular and renal impairments in DKO mice were pronounced despite lower fasting plasma glucose levels compared to lepr db/db mice, indicating that eNOS is a critical determinant of hyperglycemia-induced organ-specific complications and their severity in diabetes. Results provide the first evidence that absence of eNOS in diabetes has a greater deleterious effect on the renal microvasculature than on the larger aortic vessel. The DKO model may suggest novel therapeutic strategies to prevent both vascular and renal complications of diabetes. KEYWORDS: diabetes; endothelial dysfunction; eNOS; micro-and macrovasculature; nephropathy and vasculopathy Macro-and microangiopathy including accelerated atherosclerosis and nephropathy are the most common complications of diabetes. Reduced bioavailabilty of nitric oxide (NO), due to impaired nitric oxide synthase (NOS) activity, is implicated in the generation of these abnormalities. 1-3 NO is formed from L-Arginine by three isoforms of NOS with stoichiometric production of L-citrulline. Among the three isoforms, endothelial NOS (eNOS) is constitutively expressed predominantly in the macrovascular endothelium and along the renal microvascular tree. Basal release of eNOS-driven NO by endothelial cells contributes to the maintenance of normal vasodilatory tone and thromboresistance. Under conditions of hyperglycemia and associated increase in advanced glycation end products, there is excessive generation of superoxide, which interacts with NO resulting in the formation of peroxynitrites. The peroxynitrites oxidize tetrahydrobiopterin, an important cofactor involved in normal eNOS activity. The deficiency of tetrahydrobiopterin causes eNOS uncoupling, which results in increased generation of superoxide rather than NO. Overall, superoxide generation is amplified in macrovessels in diabetes with concomitant reduction in the level of bioavailable NO.Nitric oxide also acts as a potent modulator of renal function and controls both afferent and efferent vascular tone, glomerular ultrafiltration coefficient 4,5 and medullary blood flow. 6 However, the pr...

show abstract

“…14 Circulating peripheral blood (PB) EPCs in WT and TNFR2 KO mice were evaluated with the use of EPC culture assay and by fluorescence-activated cell sorter (FACS) analysis, as described previously. 14,15 (For additional EPC characterization, please refer to Figure IV in the online-only Data Supplement. )…”

Section: Methods Endothelial Progenitor Cell Culture and In Vitro Funmentioning

confidence: 99%

“…23,24 To assess the number of circulating BMderived EPCs in PB after hindlimb surgery in WT versus p75KO, MNCs isolated from PB were evaluated for the expression of Flk1 and Sca1 by FACS analysis. 15 Only Flk1/Sca1 double-positive cells were considered EPC and were included in our calculation ( Figure II in the onlineonly Data Supplement). FACS analysis revealed a gradual increase in circulating BM-derived EPCs in WT compared with p75KO mice between days 1 and 3, with a maximal 4-fold increase by day 3 (11.1Ϯ3.1 versus 2.6Ϯ1.8; PϽ0.05) ( Figure 1D).…”

Section: Goukassian Et Al Tnfr2/p75 and Neovascularization 753mentioning

confidence: 99%

Tumor Necrosis Factor-α Receptor p75 Is Required in Ischemia-Induced Neovascularization

Qin²,

et al. 2007

Self Cite

View full text Add to dashboard Cite

Background-Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-␣ (TNF-␣), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-␣ receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. Methods and Results-We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss. Conclusions-Our present study suggests that ischemia-induced endothelial progenitor cell-mediated neovascularization is dependent, at least in part, on p75 TNF receptor expressed in bone marrow-derived cells. Specifically, endothelial cell/endothelial progenitor cell survival, vascular endothelial growth factor expression, endothelial progenitor cell mobilization from bone marrow, endothelial progenitor cell differentiation, and ultimately ischemia-induced collateral vessel development are dependent on signaling through TNFR2/p75. Furthermore, because TNFR2/p75 becomes an age-related limiting factor in postischemic recovery, it may be a potential gene target for therapeutic interventions in adult vascular diseases. (Circulation. 2007;115:752-762.)

show abstract

Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury

Cited by 392 publications

References 37 publications

Human aging and CD31⁺T-cell number, migration, apoptotic susceptibility, and telomere length

Human aging and CD31⁺T-cell number, migration, apoptotic susceptibility, and telomere length

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Tumor Necrosis Factor-α Receptor p75 Is Required in Ischemia-Induced Neovascularization

Contact Info

Product

Resources

About

Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury

Cited by 392 publications

References 37 publications

Human aging and CD31+T-cell number, migration, apoptotic susceptibility, and telomere length

Human aging and CD31+T-cell number, migration, apoptotic susceptibility, and telomere length

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Tumor Necrosis Factor-α Receptor p75 Is Required in Ischemia-Induced Neovascularization

Contact Info

Product

Resources

About

Human aging and CD31⁺T-cell number, migration, apoptotic susceptibility, and telomere length

Human aging and CD31⁺T-cell number, migration, apoptotic susceptibility, and telomere length