Biomedical subjects

Jay M Edelberg

Publications and source records attributed to Jay M Edelberg.

At least 19 recordsLinked to original sources

PubMed2006

Bone marrow Oct3/4+ cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms.

The mechanisms that govern the capacity of the bone marrow stem cells to generate cardiac myocytes are still unknown. Herein we demonstrate that the cardiomyogenic potential of bone marrow-derived Oct3/4(+)/cKit(+/-)/CXCR4(+/-)/CD34(-)/Sca1(-) cells is governed by age-dependent paracrine/juxtacrine platelet-derived growth factor (PDGF) pathways. Specifically, bone marrow cell cultures from both 3- and 18-month-old mice formed aggregates of Oct3/4(+) cells circumscribed by PDGFRalpha(+)/Oct3/4(-)/Sca1(+) cells. In young (3-month) bone marrow cell cultures, induction of PDGF-AB preceded the induction of cardiac genes and was required for the generation of cardiomyogenesis. Indeed, in old (18-month) cultures, diminished PDGF-B induction was associated with impaired cardiomyogenic potential, despite having Oct3/4 levels similar to those in the young cells. Importantly, supplementation with PDGF-AB specifically restored the cardiac differentiation capacity of the old bone marrow cells. Together these results demonstrate that, regardless of age, the bone marrow niche contains Oct3/4 stem cells that are capable of differentiating into cardiac myocytes. Moreover, this differentiation is governed by age-dependent PDGF-AB-mediated paracrine/juxtacrine pathways that may be essential in the translation of bone marrow cell-mediated cardiomyogenesis.

Animals↗

PubMed2006

Quantitative PCR-based approach for rapid phage display analysis: a foundation for high throughput vascular proteomic profiling.

Functional proteomic strategies offer unique advantages over current molecular array approaches, as the epitopes identified can directly provide bioactive peptides for investigational and/or translational applications. The vascular endothelium is well suited to proteomic assessment by in vivo phage display, but extensive enrichment and sequencing steps limit its application for high throughput molecular profiling. To overcome these limitations we developed a quantitative PCR (Q-PCR) strategy to allow the rapid quantification of in vivo phage binding. Primers were designed for distinct clones selected from a defined phage pool to probe for age-associated changes in cardiac vascular epitopes. Sensitivity and specificity of the primer sets were tested and confirmed in vitro. Q-PCR quantification of phage in vivo confirmed the preferential homing of all phage clones to the young rather than old cardiac vasculature and demonstrated a close correlation with phage measurements previously determined using traditional bacterial-based titration methods. This Q-PCR approach provides quantification of phage within hours of phage injection and may therefore be used for rapid, high throughput analysis of binding of defined phage sequences both in vivo and in vitro, complementing nonbiased phage approaches for the proteomic mapping of vascular beds and other tissues.

Aging↗

PubMed2006

Vascular tenascin-C regulates cardiac endothelial phenotype and neovascularization.

Microenvironmental cues mediate postnatal neovascularization via modulation of endothelial cell and bone marrow-derived endothelial progenitor cell (EPC) activity. Numerous signals regulate the activity of both of these cell types in response to vascular injury, which suggests that parallel mechanisms regulate angiogenesis in the vascular beds of both the heart and bone marrow. To identify mediators of such shared pathways, in vivo bone marrow/cardiac phage display biopanning was performed and led to the identification of tenascin-C as a candidate protein. Functionally, tenascin-C inhibits cardiac endothelial cell spreading and enhances migration in response to angiogenic growth factors. Analysis of human coronary thrombi revealed tenascin-C protein expression colocalized with the endothelial cell/EPC marker Tie-2 in intrathrombi vascular channels. Immunostains in the rodent heart demonstrated that tenascin-C also colocalizes with EPCs homing to sites of cardiac angiogenic induction. To determine the importance of tenascin-C in cardiac neovascularization, we used an established cardiac transplantation model and showed that unlike wild-type mice, tenascin-C-/- mice fail to vascularize cardiac allografts. This demonstrates for the first time that tenascin-C is essential for postnatal cardiac angiogenic function. Together, our data highlight the role of tenascin-C as a microenvironmental regulator of cardiac endothelial/EPC activity.

Aging↗

PubMed2006

Cell sources for cardiac regeneration--which cells and why.

Realizing the promise of therapeutic cardiac regeneration requires the targeting of accessible cell sources to promote neomyogenesis for the injured heart. After initial trials with cardiac myocytes and skeletal muscle progenitor cells (myoblasts), the rapid advances of stem cell technology have established the feasibility of endogenous stem cells to serve as donor cells for cellular cardiomyoplasty. In particular, bone marrow-derived stem cells have a great potential for clinical application due to their extracardiac locale and capacity to give rise to functional cardiac myocytes. The recent identification of resident cardiac stem cells also offers the opportunity to regenerate the infarcted myocardium, using the cells from the heart for ex vivo expansion or as targets for in vivo induction. To this end, future advances in cellular cardiomyoplasty may likely be based on therapies stimulating the trophic/cellular interactions that direct exogenous/endogenous stem cell-mediated cardiac regeneration.

Animals↗

PubMed2005

Harnessing hormonal signaling for cardioprotection.

Cardiovascular disease is the leading cause of death in women in the Western world and is predominant among the elderly. A large body of evidence suggests that hormonal signaling plays a critical role in the regulation of cardioprotective mechanisms, as premenopausal women are at significantly lower risk of heart disease compared with men, but the risk greatly increases with the onset of menopause. This association indicates that estrogen may protect the heart from cardiovascular disease. Whereas a number of analyses of the effects of hormone replacement therapy (HRT) on postmenopausal women supported the idea that estrogen is a cardioprotective factor, the findings of the more recent Women's Health Initiative (WHI) study suggested that HRT may actually increase the risk of cardiovascular events. These conflicting reports have left both patients and clinicians reluctant to continue using current HRT regimes. The WHI findings do not, however, negate the epidemiological link between menopause and increased cardiovascular risk. Hence, the identification of the specific actions of estrogen that promote cardioprotective pathways without enhancing deleterious vascular mechanisms may provide novel estrogen-based alternatives to current HRT strategies. In this Review, we outline the known actions of estrogen on the cardiovascular system, focusing on cardioprotective mechanisms that may be targeted for the development of new therapeutic approaches.

Aged↗

PubMed2005

BDNF-mediated enhancement of inflammation and injury in the aging heart.

Aging is associated with shifts in autocrine and paracrine pathways in the cardiac vasculature that may contribute to the risk of cardiovascular disease in older persons. To elucidate the molecular basis of these changes in vivo, phage-display biopanning of 3- and 18-mo-old mouse hearts was performed that identified peptide epitopes with homology to brain-derived neurotrophic factor (BDNF) in old but not young phage pools. Quantification of cardiac phage binding by titration and immunostaining after injection with BDNF-like phage identified a twofold increased density of the BDNF receptor, truncated Trk B, in the aging hearts. Studies focused on the receptor ligand using a rat model of transient myocardial ischemia revealed increases in cardiac BDNF associated with local mononuclear infiltrates in 24- but not 4-mo-old rats. To investigate these changes, both 4- and 24-mo-old rat hearts were treated with intramyocardial injections of BDNF (or PBS control), demonstrating significant inflammatory increases with activated macrophage (ED1+) in BDNF-treated aging hearts compared with aging controls and similarly treated young hearts. Additional studies with permanent coronary occlusion following intramyocardial growth factor pretreatment revealed that BDNF significantly increased the extent of myocardial injury in older rat hearts (BDNF 35 +/- 10% vs. PBS 16.2 +/- 7.9% left ventricular injury; P < 0.05) without affecting younger hearts (BDNF 15 +/- 5.1% vs. PBS 14.5 +/- 6.0% left ventricular injury). Overall, these studies suggest that age-associated changes in BDNF-Trk B pathways may predispose the aging heart to increased injury after acute myocardial infarction and potentially contribute to the enhanced severity of cardiovascular disease in older individuals.

Aging↗

PubMed2005

Synergistic targeting with bone marrow-derived cells and PDGF improves diabetic vascular function.

Diabetes mellitus is associated with an increased risk of vascular disease, with significant alterations in systemic endothelial progenitor cells (EPCs) and peripheral vascular function. To identify the contribution of the different vascular compartments in the diabetic impairment of vascularization, we employed streptozotocin- and control-treated 3-mo-old C57Bl/6 mice in an isogeneic pinnal cardiac allograft model, revealing a significant delay in vascularization of wild-type cardiac tissue transplanted into diabetic mice. To investigate the basis of this impairment, the function of diabetic bone marrow cells was tested by transplantation of bone marrow cells isolated from diabetic and control mice into intact, unirradiated 18-mo-old C57Bl/6 mice, which have impaired function of both EPCs and peripheral endothelial cells. Importantly, cells derived from control, but not diabetic, bone marrow integrated into transplanted cardiac allografts. To assess the contribution of diabetic changes in the local vasculature, diabetic mice were treated with pinnal injections of platelet-derived growth factor (PDGF)-AB, which promotes cardiac angiogenesis in wild-type mice. However, whereas PDGF-AB enhanced allograft function in control mice, the activity of the cardiac transplants in the PDGF-AB-treated diabetic mice was significantly decreased. To decipher the potential interactions between systemic bone marrow-derived cells and local vascular pathways, diabetic mice were transplanted with wild-type bone marrow cells with or without PDGF-AB pinnal pretreatment, resulting in improved allograft function and donor cell recruitment only in the combination treatment arm. Overall, these studies show that the diabetic impairment in cardiac angiogenesis can be reversed by targeting the synergism between local trophic pathways and systemic cell function.

Animals↗

PubMed2005

PDGF-AB-based functional cardioprotection of the aging rat heart.

Recent studies have demonstrated that targeting of an age-associated impairment in platelet-derived growth factor (PDGF-AB) pathways could reduce histological measures of myocardial infarction in aging rat hearts. To facilitate preclinical developments of this approach, non-invasive measures of cardiac function were investigated in a 24-month-old rat myocardial infarction model employing intramyocardial PDGF-AB (100 ng) or vehicle control pretreatment. Electrocardiographic recordings post-coronary occlusion revealed ST segment elevation-myocardial injury patterns in both groups, which was confirmed histologically 2 weeks later by Masson's trichrome stains (PDGF-AB, 14.6+/-2.8% of left ventricular area (LVA) vs. control, 27.9+/-9.2%; P<0.05). Echocardiographic fractional shortening (FS) measurements revealed greater preservation of cardiac function in PDGF-AB-treated hearts compared with controls (PDGF-AB FS: 27.3+/-3.7% vs. control--16.7+/-4.1% (ANOVA P=0.005) vs. sham operation--34.5+/-6.7%), with a significant inverse relationship between FS and extent of myocardial injury (m=-0.68; r=-0.84). Notably, exercise testing did not correlate with myocardial injury. These findings provide an important functional foundation in preclinical translations of PDGF-AB-based cardioprotective treatment strategies. Moreover, demonstration of respective roles of electrocardiography and echocardiography in the confirmation and correlation of myocardial injury in the aging rat heart may serve to facilitate both PDGF-AB-based and other age-targeted approaches in large animal models of aging and cardiovascular disease.

Aging↗

PubMed2005

Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection.

Based on the role of tumor necrosis factor-alpha (TNF-alpha) in ischemic preconditioning (IPC) and the age-associated loss of both TNF-alpha-induced platelet-derived growth factor-AB (PDGF-AB)-mediated cardioprotection and IPC-mediated cardioprotection, we hypothesized that targeting of PDGF-AB-based pathways would restore cardioprotection by IPC in the aging heart. To study this, IPC was induced in 4- and 24-mo-old F344 rats. Sections of young hearts isolated 1 day post-IPC revealed increased TNF-alpha compared with controls. In old rats, TNF-alpha was higher at baseline than IPC young rats and was not significantly altered after IPC. Treatment of old rats with PDGF-AB with vascular endothelial growth factor and angiopoietin-2 (a combination termed PVA), but not PDGF-AB alone, at the time of IPC decreased TNF-alpha. In addition, when compared with young hearts, IPC induced greater apoptosis in the old hearts, which was decreased with PVA treatment but was markedly increased with PDGF-AB. To test the significance of these findings, additional rats underwent permanent coronary ligation 1 day post-IPC. IPC was cardioprotective in young rats [14 days postmyocardial infarction (MI), fractional shortening 29 +/- 6% vs. control MI 17 +/- 4%, P < 0.05; Masson's trichrome stain MI size: 13 +/- 2% vs. control MI 17 +/- 4% left ventricular area (LVA); P < 0.05]. In old rats, however, IPC reduced the post-MI 14-day survival (33% vs. controls 67%; P < 0.05). Treatment of IPC-aging rats with PVA, but not PDGF-AB-alone, reversed IPC-induced mortality (PVA-IPC-MI survival, 88%; PDGF-AB-IPC-MI, 14%) and reduced myocardial injury (fractional shortening: PVA-IPC, 31 +/- 1% vs. control MI, 21 +/- 6%, P < 0.05; MI size: PVA-IPC, 12 +/- 2% vs. control MI, 18 +/- 3% LVA, P < 0.05) and thus demonstrated that PDGF-AB-based pathways can reverse the senescent impairment in IPC-mediated cardioprotection.

Aging↗

PubMed2005

Cytokine preconditioning promotes codifferentiation of human fetal liver CD133+ stem cells into angiomyogenic tissue.

BACKGROUND: CD133 (AC133) is a surface antigen that defines a broad population of stem cells, including myogenic and endothelial progenitors. CD133+ cells are rare in adult tissues, and the factors that support their differentiation into mature angiomyogenic cells are not known. These hurdles have hampered the use of CD133+ cells for therapeutic purposes. Because human fetal liver is a rich source of CD133+ cells, we sought to identify the growth factors that promote codifferentiation of these cells into angiogenic and myogenic cells. METHODS AND RESULTS: Human fetal liver CD133+ and CD133- cell subpopulations were cultured with 5'-azacytidine or vascular endothelial growth factor (VEGF165) and/or brain-derived nerve growth factor (BDNF). CD133+ but not CD133- cells from human fetal liver codifferentiated into spindle-shaped cells, as well as flat adherent multinucleated cells capable of spontaneous contractions in culture. The resulting spindle-shaped cells were confirmed to be endothelial cells by immunohistochemistry analysis for von Willebrand factor and by acetylated LDL uptake. Multinucleated cells were characterized as striated muscles by electron microscopy and immunohistochemistry analysis for myosin heavy chain. Presence of VEGF165 and BDNF significantly enhanced angiomyogenesis in vitro. Inoculation of cells derived from CD133+ cells, but not CD133- cells, into the ear pinna of NOD/SCID mice resulted in the formation of cardiomyocytes, as identified by immunostaining with cardiac troponin-T antibody. These cells generated electrical action potentials, detectable by ECG tracing. CONCLUSIONS: CD133 defines a population of human fetal liver cells capable of differentiating into both angiogenic and myogenic cells. Preconditioning of these CD133+ cells with VEGF165 and BDNF enhances the angiomyogenesis. CD133+ fetal liver cells ultimately may be used for therapeutic angiomyogenesis.

AC133 Antigen↗

PubMed2005

A potent opiate agonist protects against myocardial stunning during myocardial ischemia and reperfusion in rats.

OBJECTIVE: Opioids have a cardioprotective effect during ischemia. Previously, we showed in an ex-vivo model of myocardial ischemia and reperfusion that 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2, a highly potent and long-acting opioid peptide analgesic with fewer side effects than morphine, provides improved cardioprotection compared with morphine. The purpose of this study was to confirm, in an in-vivo model, the cardioprotective effect of 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2. METHODS: Rats (n=6/group) were randomized to 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 therapy (intravenous 10 nmol bolus 30 min before ligation and 10 nmol/h continuous infusion), morphine (100 nmol bolus and 100 nmol/h infusion), or placebo, and underwent left anterior descending (LAD) ligation for 10 min followed by reperfusion for 30 min. Continuous transesophageal echocardiogram and electrocardiogram were monitored. Fractional shortening and systolic wall thickening of the ischemic area were calculated. Time to recovery of left ventricular function was the duration of time needed for fractional shortening to recover to 90% of baseline following reperfusion. Duration of reperfusion arrhythmia was the time to the cessation of salvo (at least three consecutive premature ventricular contractions (PVCs)) following reperfusion. RESULTS: Time to recovery of left ventricular function was significantly shorter in the 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 (4.4+/-2.2 min) and morphine groups (6.0+/-2.5 min) than in the controls (10.5+/-2.2 min; p<0.01). The 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 group showed significantly higher fractional shortening and systolic wall thickening of the ischemic area than the control group. Duration of reperfusion arrhythmia was also significantly shorter in the 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 (2.8+/-1.7 min) and morphine groups (5.8+/-3.9 min) than in the controls (11.8+/-2.0 min; p<0.05). CONCLUSION: 2',6'-Dimethyltyrosine-D-Arg-Phe-Lys-NH2 provides a cardioprotective effect against myocardial ischemia and reperfusion in vivo.

Animals↗

PubMed2004

Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice.

Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by cardiac and extracardiac myxomas in the setting of spotty skin pigmentation and endocrinopathy. We previously identified PRKAR1A (regulatory subunit 1alpha of protein kinase A) mutations in CNC. Mutational analyses of the PRKAR1A gene in 51 unrelated CNC probands now detect mutations in 65%. All mutations, except for one unique missense mutation, lead to PRKAR1A haploinsufficiency. Therefore, we studied the consequences of prkar1a haploinsufficiency in mice. Although we did not observe cardiac myxomas or altered pigmentation in prkar1a(+/-) mice, we did observe some phenotypes similar to CNC, including altered heart rate variability. Moreover, prkar1a(+/-) mice exhibited a marked propensity for extracardiac tumorigenesis. They developed sarcomas and hepatocellular carcinomas. Sarcomas were frequently associated with myxomatous differentiation. Tumors from prkar1a(+/-) mice did not exhibit prkar1a loss of heterozygosity. Thus, we conclude that although PRKAR1A haploinsufficiency does predispose to tumorigenesis, distinct secondary genetic events are required for tumor formation.

Alleles↗

PubMed2004

Phage display identification of age-associated TNFalpha-mediated cardiac oxidative induction.

Age-associated alterations in the actions of tumor necrosis factor-alpha (TNFalpha) in the heart with impaired cardioprotective pathways and enhanced apoptotic induction may contribute to the increased severity of cardiovascular pathology in older persons. To identify the molecular events mediating these changes in the microvasculature of the aging rodent heart, the biochemical properties of in vivo phage-display cyclic peptide cardiac biopanning were studied. Analysis of individual amino acid positions revealed that the center of the peptide motif (amino acid position 4) had a significantly higher frequency of aromatic amino acid side chains in phage homing to the old hearts compared with young controls (18 mo old, 11% vs. 3 mo old, 3%, P < 0.05). This subset of phage motifs revealed an age-associated homology with oxidoreductase enzymes (homology: 18 mo, 7/7; 3 mo, 0/2), suggesting the substrates and/or binding sites of these enzymes are increased in the aging hearts. Immunostaining for the oxidoreductase substrate 4-hydroxy-2-nonenal (HNE), a cardiotoxic lipid peroxidation product, demonstrated a twofold higher density of HNE(+) cells in PBS-treated hearts of old mice (18 mo) compared with young controls (3 mo) (18 mo, 3.2 +/- 2.8 vs. 3 mo, 1.0 +/- 0.9 cells/HPF, P < 0.05). Moreover, intracardiac injection of TNFalpha resulted in a significantly greater increase in HNE staining in the old hearts (18 mo, 16.9 +/- 13.8 vs. 3 mo, 9.1 +/- 6.0 cells/HPF, P < 0.05). Overall, these studies demonstrate that aging-associated alterations in TNFalpha-mediated pathways with induction of reactive oxidative species and changes in vascular surface binding sites may contribute mechanistically to the increased cardiovascular pathology of the aging heart.

Aging↗

PubMed2004

Senescent impairment in synergistic cytokine pathways that provide rapid cardioprotection in the rat heart.

Pretreatment of rodent hearts with platelet-derived growth factor (PDGF)-AB decreases myocardial injury after coronary occlusion. However, PDGF-AB cardioprotection is diminished in older animals, suggesting that downstream elements mediating and/or synergizing the actions of PDGF-AB may be limited in aging cardiac vasculature. In vitro PDGF-AB induced vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 expression in 4-mo-old rat cardiac endothelial cells, but not in 24-mo-old heart cells. In vivo injection of young hearts with PDGF-AB increased densities of microvessels staining for VEGF and its receptor, Flk-1, and Ang-2 and its receptor, Tie-2, as well as PDGF receptor (PDGFR)-alpha. In older hearts, PDGF-AB-mediated induction was primarily limited to PDGFR-alpha. Studies in a murine cardiac transplantation model demonstrated that synergist interactions of PDGF-AB plus VEGF plus Ang-2 (PVA) provided an immediate restoration of senescent cardiac vascular function. Moreover, PVA injection in young rat hearts, but not PDGF-AB alone or other cytokine combinations, at the time of coronary occlusion suppressed acute myocardial cell death by >50%. However, PVA also reduced the extent of myocardial infarction with an age-associated cardioprotective benefit (4-mo-old with 45% reduction vs. 24-mo-old with 24%; P < 0.05). These studies showed that synergistic cytokine pathways augmenting the actions of PDGF-AB are limited in older hearts, suggesting that strategies based on these interactions may provide age-dependent clinical cardiovascular benefit.

Aging↗

PubMed2004

Impaired angiogenesis in the aged.

The process of angiogenesis, during which new blood vessels are formed, is impaired during aging. This Perspective describes many of the myriad components of the angiogenic response that are altered with age. In addition, the impact of impaired angiogenesis on wound healing, vascular disease, and cancer in the aged is discussed.

Aged↗

PubMed2004

Platelet-derived growth factor-AB promotes the generation of adult bone marrow-derived cardiac myocytes.

The directed generation of cardiac myocytes from endogenous stem cells offers the potential for novel therapies for cardiovascular disease. To facilitate the development of such approaches, we sought to identify and exploit the pathways directing the generation of cardiac myocytes from adult rodent bone marrow cells (BMCs). In vitro cultures supporting the spontaneous generation of functional cardiac myocytes from murine BMCs demonstrated induced expression of platelet-derived growth factor (PDGF)-A and -B isoforms with alpha- and beta-myosin heavy chains as well as connexin43. Supplementation of PDGF-AB speeded the kinetics of myocyte development in culture by 2-fold. In a rat heart, myocardial infarction pretreatment model PDGF-AB also promoted the derivation of cardiac myocytes from BMCs, resulting in a significantly greater number of islands of cardiac myocyte bundles within the myocardial infarction scar compared with other treatment groups. However, gap junctions were detected only between the cardiac myocytes receiving BMCs alone, but not BMCs injected with PDGF-AB. Echocardiography and exercise testing revealed that the functional improvement of hearts treated with the combination of BMCs and PDGF-AB was no greater than with injections of BMCs or PDGF-AB alone. These studies demonstrated that PDGF-AB enhances the generation of BMC-derived cardiac myocytes in rodent hearts, but suggest that alterations in cellular patterning may limit the functional benefit from the combined injection of PDGF-AB and BMCs. Strategies based on the synergistic interactions of PDGF-AB and endogenous stem cells will need to maintain cellular patterning in order to promote the restoration of cardiac function after acute coronary occlusion.

Animals↗

PubMed2004

Platelet-derived growth factor improves cardiac function in a rodent myocardial infarction model.

OBJECTIVES: The translation of cardioprotective therapies for myocardial infarction requires a preclinical demonstration of improved cardiovascular function following acute coronary occlusion. We previously showed that pretreatment of rodent hearts with platelet-derived growth factor (PDGF) promotes angiogenesis and decreases the extent of myocardial injury measured by histology. The present study aimed to determine the correlation of these histological findings with noninvasive measures of improvement in cardiac function. METHODS: Rats were treated with intramyocardial injections of PDGF (100 ng) or phosphate buffer solution (PBS) (n = 6 per group) 24 h prior to acute, permanent ligation of the left anterior descending artery and the extent of myocardial injury was assessed by Masson's trichrome staining 14 days later. To assess the physiological effects of PDGF pretreatment after coronary occlusion, cardiac function was assessed noninvasively by electrocardiography, exercise testing and echocardiography and correlated with direct histological measures. RESULTS: Physiological studies demonstrated that PDGF resulted in lower ST-segment elevation at the time of coronary occlusion (0.12 +/- 0.02 mV above baseline) than in PBS control rats (0.35 +/- 0.05 mV; P < 0.05). Exercise testing 14 days after coronary occlusion revealed that PDGF pretreatment resulted in faster maximal exercise speeds (28.54 +/- 3.98 m/min) than in control rats (24.98 +/- 3.13 m/min; P < 0.05). Echocardiography also revealed that the left ventricular factional shortening in the PDGF-pretreated rats was significantly greater (18.47 +/- 12.21%) than in control animals (4.91 +/- 7.21%; P<0.05). CONCLUSIONS: These studies demonstrate that PDGF pretreatment improves cardiac function following acute coronary occlusion. Strategies based on the cardioprotective actions of PDGF may provide a significant advance in the treatment of myocardial infarction.

Animals↗

PubMed2003

Aging and angiogenesis.

Angiogenesis is impaired in aged tissues. It is probable that this deficit contributes to the increased severity of vascular diseases observed in older persons. The changes in angiogenesis that occur with aging have been noted at the molecular, cellular, and physiologic levels of regulation. Components of the neovascular process that are influenced by age include endothelial cells, the hemostatic cascade, neuro-chemical mediators, and growth factors and their cognate receptors. The structural and regulatory components of the matrix scaffold that surround newly formed vessels is also altered in aged tissues. These myriad changes result in delayed and impaired neovascularization. The clinical consequences of the decreased potential of aged tissues to form new vessels is detrimental during the revascularization of the ischemic heart and during the repair of injured tissues, but may be of benefit in slowing the growth of tumors. In this context, clinical strategies to improve the function of the aging vasculature in general, and the angiogenic response in particular, must be targeted to specific disease states in order to maximize the potential benefit to older individuals.

Aging↗