RESUMO
The assumption that the coronary capillary blood flow is exclusively regulated by precapillary vessels is not supported by recent data. Rather, the complex coronary capillary bed has unique structural and geometric characteristics that invalidate many assumptions regarding red blood cell (RBC) transport, for example, data based on a single capillary or that increases in flow are the result of capillary recruitment. It is now recognized that all coronary capillaries are open and that their variations in flow are due to structural differences, local O2 demand and delivery, and variations in hematocrit. Recent data reveal that local mechanisms within the capillary bed regulate flow via signaling mechanisms involving RBC signaling and endothelial-associated pericytes that contract and relax in response to humoral and neural signaling. The discovery that pericytes respond to vasoactive signals (e.g., nitric oxide, phenylephrine, and adenosine) underscores the role of these cells in regulating capillary diameter and consequently RBC flux and oxygen delivery. RBCs also affect blood flow by sensing P O 2 and releasing nitric oxide to facilitate relaxation of pericytes and a consequential capillary dilation. New data indicate that these signaling mechanisms allow control of blood flow in specific coronary capillaries according to their oxygen requirements. In conclusion, mechanisms in the coronary capillary bed facilitate RBC density and transit time, hematocrit, blood flow and O2 delivery, factors that decrease capillary heterogeneity. These findings have important clinical implications for myocardial ischemia and infarction, as well as other vascular diseases.
Assuntos
Capilares , Óxido Nítrico , Adenosina , Eritrócitos/fisiologia , Oxigênio , FenilefrinaRESUMO
Exogenous bone marrow-derived cells (BMDCs) are promising therapeutic agents for the treatment of tissue ischemia and traumatic injury. However, until we identify the molecular mechanisms that underlie their actions, there can be no rational basis for the design of therapeutic strategies using BMDCs. The pro-healing effects of BMDCs are apparent very shortly after treatment, which suggests that they may exert their effects by the modulation of acute inflammation. We investigated this hypothesis by taking advantage of the fact that BMDCs from healthy, young, but not obese, diabetic mice stimulate vascular growth. By comparing both in vitro secretion and in vivo local induction of acute phase inflammatory cytokines by these cells, we identified monocyte chemoattractant factor 1 and tumor necrosis factor α as potential mediators of BMDC-induced tissue repair. In vivo analysis of BMDC-treated ischemic limbs and cutaneous wounds revealed that the production of monocyte chemoattractant factor 1 by exogenous and endogenous BMDCs is essential for BMDC-mediated vascular growth and tissue healing, while the inability of BMDCs to produce tumor necrosis factor α appears to play a lesser but still meaningful role. Thus, measurements of the secretion of cytokines by BMDCs may allow us to identify a priori individuals who would or would not be good candidates for BMDC-based therapies.
Assuntos
Medula Óssea/metabolismo , Medula Óssea/patologia , Quimiocina CCL2/metabolismo , Inflamação/prevenção & controle , Isquemia/prevenção & controle , Receptores para Leptina/metabolismo , Cicatrização , Animais , Western Blotting , Células Cultivadas , Citocinas/metabolismo , Extremidades , Técnicas Imunoenzimáticas , Inflamação/etiologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Isquemia/etiologia , Isquemia/metabolismo , Camundongos , Camundongos Knockout , Pele/lesões , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
In embryonic hearts explanted on collagen gels, epicardial cells delaminate and form vascular tubes, thus providing a model for coronary tubulogenesis. Using this model, we show that fibroblast growth factors (FGFs) 1, 2, 4, 8, 9, and 18 contribute to tubulogenesis and that the availability of multiple FGFs provides the optimal tubulogenic response. Moreover, the FGF effects are vascular endothelial growth factor (VEGF) -dependent, while VEGF-induced tubulogenesis requires FGF signaling. The number of endothelial cells (ECs) is increased by all of the FGFs, while EC migration is significantly enhanced only by FGF-2 and FGF-18. Finally, addition of embryonic mesenchymal stem cells (EMSC) to the explants markedly enhances EC numbers and a 23-fold increase in stromal derived factor-1α (SDF-1α), which is FGF dependent. Both explants and EMSCs produce SDF-1α. In conclusion, coronary tubulogenesis of embryonic epicardium: (1) is responsive to many FGF family members, (2) requires both FGF and VEGFA signaling, and (3) is responsive to EMSCs.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Células-Tronco Mesenquimais/fisiologia , Neovascularização Fisiológica/fisiologia , Pericárdio/embriologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Movimento Celular/fisiologia , Células Endoteliais/citologia , Transição Epitelial-Mesenquimal/fisiologia , Células-Tronco Mesenquimais/citologia , Camundongos , CodornizRESUMO
We compared the effects of heart rate reduction (HRR) by the hyperpolarization-activated pacemaker current (I(f)) channel inhibitor ivabradine (MI+Iva) and the beta(1)-blocker atenolol (MI+Aten) on ventricular remodeling and perfusion after myocardial infarction (MI) in middle-aged (12 mo) Sprague-Dawley rats. Mean HRR was virtually identical in the two treated groups (19%). Four weeks after coronary artery ligation, maximal myocardial perfusion fell in the MI group but was preserved in infarcted rats treated with either Iva or Aten. However, coronary reserve in the remodeled hearts was preserved only with Iva, since Aten treatment elevated baseline perfusion in response to a higher wall stress. The higher maximal perfusion noted in the two treated groups was not due to arteriogenesis or angiogenesis. Plasma levels of angiotensin (ANG) II and myocardial ANG type 1 (AT(1)) receptor and transforming growth factor (TGF)-beta1 were reduced during the first week of treatment by both Iva and Aten. Moreover, treatment also reduced arteriolar perivascular collagen density. Despite these similar effects of Iva and Aten on vascularity and ANG II, Iva, but not Aten, attenuated the decline in ejection fraction and lowered left ventricular (LV) end-diastolic volume (LVEDV)-to-LV mass ratio, determined by echocardiography. In conclusion, 1) Iva has advantages over Aten in postinfarction therapy that are not due to differential effects of the drugs on heart rate, and 2) age limits growth factor upregulation, angiogenesis, and arteriogenesis in the postinfarcted heart.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Atenolol/uso terapêutico , Benzazepinas/uso terapêutico , Cardiotônicos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Remodelação Ventricular/fisiologia , Angiotensina II/biossíntese , Angiotensina II/fisiologia , Animais , Bradicinina/metabolismo , Colágeno/metabolismo , Circulação Coronária/efeitos dos fármacos , Eletrocardiografia , Frequência Cardíaca/efeitos dos fármacos , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ivabradina , Masculino , Infarto do Miocárdio/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Tamanho do Órgão , Perfusão , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/biossíntese , Receptor Tipo 1 de Angiotensina/fisiologiaRESUMO
OBJECTIVE: PDGF and FGF-2 are important regulators of vascular wall assembly. We tested the hypothesis that their embryonic temporal expression facilitates 2 specific events: (1) the endothelial invasion of the aortic root to form the coronary artery stems and (2) the subsequent growth and development of the arterial tree. METHODS AND RESULTS: Addition of FGF-2 and PDGF-BB proteins to embryonic quail heart explants stimulated a 3- and 7-fold increase, respectively, in tubulogenesis, whereas neutralizing antibodies to these growth factors attenuated tubulogenesis by 40%. Anti-FGF-2 and anti-PDGF neutralizing antibodies were then introduced in ovo via the vitelline vein at various embryonic (E) days. When injections occurred before coronary ostial formation, the embryos usually developed only 1 coronary artery or lacked coronary arteries. When 1 or both major coronary arteries formed: (1) their branches had a thinner tunica media, and (2) smooth muscle investment did not progress as far distally as in shams. Other anomalies included smaller diameter coronary artery stems in some hearts. Inhibition of VEGF via injections of aflibercept (VEGF-Trap, a VEGFR-1 and -2 chimera), previously shown to be essential for coronary stem formation, limited development of the coronary arteries even though introduced after formation of coronary ostia (at E9 or EI0). CONCLUSIONS: Our data (1) document a role for FGF-2 and PDGF in the temporal regulation of coronary artery stem formation and growth of the coronary arterial tree and (2) reveal that VEGF expression is required for normal artery/arterial formation, even after coronary artery stem formation.
Assuntos
Vasos Coronários/metabolismo , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neovascularização Fisiológica , Fator de Crescimento Derivado de Plaquetas/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Anticorpos , Becaplermina , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/embriologia , Vasos Coronários/crescimento & desenvolvimento , Fator 2 de Crescimento de Fibroblastos/imunologia , Humanos , Neovascularização Fisiológica/efeitos dos fármacos , Fenótipo , Fator de Crescimento Derivado de Plaquetas/imunologia , Proteínas Proto-Oncogênicas c-sis , Codorniz , Proteínas Recombinantes/metabolismo , Projetos de Pesquisa , Transdução de Sinais , Fatores de Tempo , Técnicas de Cultura de Tecidos , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
This study tested the hypothesis that coronary tubulogenesis and coronary artery formation require VEGF family members. Quail embryos were injected with soluble vascular endothelial growth factor (VEGF) receptors R1 (Flt-1), R2 (Flk-1), R3 (Flt-4), VEGF-Trap (a chimera of R1 and R2), or neutralizing antibodies to VEGF-A, VEGF-B, or fibroblast growth factor (FGF)-2. Our data document that tubulogenesis is temporally dependent on multiple VEGF family members, because the early stage of tubulogenesis was markedly inhibited by VEGF-Trap and to a lesser extent by soluble VEGFR-1. Some inhibition of tubulogenesis was documented when anti-FGF-2, but not anti-VEGF-A, antibodies were injected at embryonic day 6 (E6). Most importantly, we found that VEGF-Trap injected at either E6 or E7 prevented the formation of coronary arteries. Soluble VEGFR-1 and soluble VEGFR-2 modified the formation of coronary arteries, whereas soluble VEGFR-3 was without effect. Antibodies to VEGF-B, but not VEGF-A, had a strong inhibitory effect on coronary artery development. The absence of coronary artery stems, and thus a functional coronary circulation, in the embryos injected with VEGF-Trap caused an accumulation of erythrocytes in the subepicardium and muscular interventricular septum. Using retroviral cell tagging, we showed that some of the erythrocytes in blood islands and small vascular tubes were progeny of the proepicardium. Thus, another salient finding of this study is the first definitive documentation of proepicardially derived hemangioblasts, which can differentiate into erythrocytes.
Assuntos
Vasos Coronários/embriologia , Embrião não Mamífero/fisiologia , Coração/embriologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Apoptose , Vasos Coronários/citologia , Coturnix , Fator 2 de Crescimento de Fibroblastos , Humanos , Microtúbulos/fisiologia , TransfecçãoRESUMO
BACKGROUND: Despite an appreciable increase in basal coronary blood flow in cyanotic congenital heart disease, flow reserve remains normal. We hypothesized that preservation of flow reserve resides in remodeling of the coronary microcirculation. Microcirculatory morphometric analyses were performed to test this hypothesis. METHODS AND RESULTS: Necropsy specimens from 4 sources were studied: (1) hearts from patients with Eisenmenger's syndrome (A; n=5), (2) structurally abnormal hearts with ventricular hypertrophy (B; n=8), (3) structurally normal hearts with ventricular hypertrophy (C; n=6), and (4) normal hearts (D; n=5). To compare responses of the microcirculation to hypoxia versus hypertrophy, sections were taken from the left ventricular free wall, which in group A, was hypoxemic but not hypertrophied; in groups B and C, was hypertrophied but not hypoxemic; and in group D, was neither hypertrophied nor hypoxemic. Coronary arterioles were immunolabeled for smooth muscle alpha-actin. Measured morphometric parameters included long and short axes, area, and perimeter. Arteriolar length, volume and surface densities were calculated. There was a significant intergroup difference for arteriolar length density (P=0.03) and diameter (P=0.03). Total length density in group A hearts was markedly lower, but mean arteriolar diameter was significantly greater (34%) compared with group B (P=0.03). Arteriolar volume density was similar to that in the other groups. CONCLUSIONS: Remodeling of the coronary microcirculation is the key mechanism for preservation of flow reserve in cyanotic congenital heart disease. The increase in short axis (diameter) compensated for lower arteriolar length density and was the principal anatomic basis for maintenance of normal flow reserve.
Assuntos
Circulação Coronária/fisiologia , Cianose/fisiopatologia , Cardiopatias Congênitas/fisiopatologia , Microcirculação/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Vasos Coronários/patologia , Vasos Coronários/fisiopatologia , Complexo de Eisenmenger/patologia , Complexo de Eisenmenger/fisiopatologia , Humanos , Prontuários Médicos , Modelos Anatômicos , Estudos RetrospectivosRESUMO
OBJECTIVE: Peripheral blood contains primitive (stem cell-like) and monocytic-like endothelial cell progenitors. Diabetes apparently converts these primitive progenitors, from a pro-angiogenic to anti-angiogenic phenotype. Monocytic progenitors seem to be less affected by diabetes, but potential pro-angiogenic activities of freshly isolated monocytic progenitors remain unexplored. We compared the ability of primitive and monocytic endothelial cell progenitors to stimulate vascular growth and healing in diabetes and investigated potential molecular mechanisms through which the cells mediate their in vivo effects. METHODS AND RESULTS: Human CD34+ primitive progenitors and CD14+ monocytic progenitors were injected locally into the ischemic limbs of diabetic mice. CD14+ cell therapy improved healing and vessel growth, although not as rapidly or effectively as CD34+ cell treatment. Western blot analysis revealed that cell therapy modulated expression of molecules in the VEGF, MCP-1, and angiopoietin pathways. CONCLUSIONS: Injection of freshly isolated circulating CD14+ cells improves healing and vascular growth indicating their potential for use in acute clinical settings. Importantly, CD14+ cells could provide a therapeutic option for people with diabetes, the function of whose CD34+ cells may be compromised. At least some progenitor-induced healing probably is mediated through increased sensitivity to VEGF and increases in MCP-1, and possibly modulation of angiopoietins.
Assuntos
Diferenciação Celular , Diabetes Mellitus Experimental/fisiopatologia , Endotélio Vascular/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Monócitos/fisiologia , Neovascularização Fisiológica , Animais , Antígenos CD34 , Células Cultivadas , Diabetes Mellitus Experimental/patologia , Endotélio Vascular/patologia , Extremidades/irrigação sanguínea , Células-Tronco Hematopoéticas/patologia , Humanos , Isquemia/terapia , Receptores de Lipopolissacarídeos , Masculino , Camundongos , Camundongos Nus , Monócitos/patologia , Transplante de Células-Tronco , CicatrizaçãoRESUMO
Recent studies have provided insights into specific events that contribute to vasculogenesis and angiogenesis in the developing coronary vasculature. This study focused on the developmental progression of coronary vascularization beginning with tube formation and ending with the establishment of a coronary arterial tree. We used electron microscopy, histology of serial sections, and immunohistochemistry in order to provide a comprehensive view of coronary vessel formation during the embryonic and fetal periods of the quail heart, a species that has been used in a number of studies addressing myocardial vascularization. Our data reveal features of progenitor cells and blood islands, tubular formation, and the anatomical relationship of a transformed periarterial tubular network and sympathetic ganglia to the emergence and branching of the right and left coronary arteries. We have traced the pattern of coronary artery branching and documented its innervation. Finally, our data include the relationship of fibronectin, laminin, and apoptosis to coronary artery growth. Our findings bring together morphological events that occur over the embryonic and fetal periods and provide a baseline for studies into the mechanisms that regulate the various events that occur during these time periods.
Assuntos
Padronização Corporal/fisiologia , Circulação Coronária/fisiologia , Vasos Coronários/embriologia , Coração/embriologia , Codorniz/embriologia , Animais , Apoptose , Biomarcadores/metabolismo , Vasos Coronários/inervação , Vasos Coronários/metabolismo , Desenvolvimento Embrionário/fisiologia , Desenvolvimento Fetal/fisiologia , Técnica Indireta de Fluorescência para Anticorpo , Coração/inervação , Humanos , Técnicas Imunoenzimáticas , Microscopia Eletrônica de Transmissão , Miocárdio/metabolismo , Neovascularização Fisiológica/fisiologia , Pericárdio/embriologia , Codorniz/crescimento & desenvolvimentoRESUMO
OBJECTIVE: In cultured endothelium, stretch induces release of growth factors that contribute to angiogenesis. We tested the hypothesis that bradycardia, which prolongs ventricular diastolic filling time and volume, promotes collateral vessel growth. METHODS AND RESULTS: An ameroid occluder was placed on coronary arteries of dogs with normal heart rates (AM) or bradycardia (55 bpm; AM+BC). A third group had normal heart rates and no ameroid (control [CON]). Four weeks after occluder placement, myocardial blood flow at rest and maximal vasodilation (adenosine) at equivalent heart rates and vascular morphometry of hearts were measured. In AM dogs, conductance (myocardial flow/diastolic pressure) of collateral-dependent myocardium was similar to collateral-independent myocardium during rest but increased to only one third of CON during maximal vasodilation. In contrast, in AM+BC dogs, conductance was similar in collateral-dependent and -independent regions during maximal vasodilation. Arteriolar length density in collateral-dependent myocardium was 80% greater in AM+BC than AM dogs. Capillary length density in collateral-dependent region of AM dogs was lower than CON but normal in AM+BC dogs. The angiopoietin receptor Tie-2 increased in collateral-dependent regions of AM and AM+BC groups, whereas vascular endothelial growth factor increased in collateral-dependent and -independent regions only in AM+BC dogs. CONCLUSIONS: Chronic bradycardia during gradual coronary artery occlusion facilitates angiogenesis/arteriogenesis in collateral-dependent myocardium and preserves maximal perfusion.
Assuntos
Bradicardia/fisiopatologia , Circulação Coronária/fisiologia , Doença das Coronárias/fisiopatologia , Neovascularização Fisiológica/fisiologia , Animais , Arteríolas/fisiologia , Capilares/fisiologia , Doença Crônica , Vasos Coronários/fisiologia , Diástole/fisiologia , Cães , Receptor TIE-2/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Although considerable advances in our understanding of mammalian and avian embryonic coronary development have occurred during the last decade, our current knowledge of this topic in humans is limited. Accordingly, the aim of this study was to determine if the development of the human coronary vasculature in humans is like that of other mammals and avians. The data document a progression of events involving mesenchymal cell-containing villi from the proepicardium, establishment of blood islands and a capillary network. The major finding of the study is direct evidence that the capillary plexus associated with spindle cells and erythroblasts invades the base of the aorta to form coronary ostia. A role for the dorsal mesocardium is also indicated by the finding that cells from this region are continuous with the aorta and pulmonary artery. The development of the tunica media of the coronary arteries follows the same base-apex progression as in other species, with the development of branches occurring late in the embryonic period. The fetal period is characterized by 1) growth and a numerical increase in the smallest arterial branches, veins, and venules, 2) innervation of arteries, and 3) inclusion of elastic fibers in the tunica media of the coronary arteries and development of the tunica adventitia. In conclusion, the data demonstrate that the development of the coronary system in humans is similar to that of other mammalian and avian species, and for the first time documents that the formation of the ostia and coronary stems in humans occurs by ingrowth of a vascular plexus and associated cells from the epicardium.
Assuntos
Vasos Coronários/embriologia , Endotélio Vascular/embriologia , Feto/embriologia , Coração/embriologia , Humanos , Processamento de Imagem Assistida por Computador , MicroscopiaRESUMO
BACKGROUND: We tested the hypothesis that induction of chronic bradycardia would trigger an upregulation of key growth factors and receptors, which would then lead to angiogenesis and improve coronary reserve in the left ventricle after myocardial infarction. METHODS AND RESULTS: Bradycardia was induced in rats by administering alinidine via osmotic pumps beginning 1 day after coronary artery ligation. Echocardiographic analysis was conducted before and after treatment. Morphometric analysis was used in perfusion-fixed hearts to document arteriolar and capillary growth. Western blots were used to evaluate growth factor and receptor changes. During the first week of treatment, vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt-1), and basic fibroblast growth factor proteins were higher in the treated group, whereas VEGF receptor 2 (Flk-1), angiopoietin-1, and angiopoietin-2 were not affected by treatment. After 3 weeks, VEGF protein remained elevated, and bradycardia was associated with a higher capillary length density in the border (40%) and remote (14%) regions and a higher arteriolar length density in the septum (62%), despite a greater increase in left ventricular mass. Although arteriolar length density increased in all size classes, the greatest increase occurred in the smallest (terminal) arterioles. This vascular growth was associated with a 23% greater coronary reserve. Echocardiography revealed a smaller increase in ventricular volume and a greater preservation of ejection fraction in rats treated with bradycardia. CONCLUSIONS: Pharmacologic induction of bradycardia enhances vascularity and coronary reserve, preserves function of surviving myocardium, and therefore, is a noninvasive, therapeutic avenue that provides an alternative to gene therapy.
Assuntos
Angiopoietina-1/análogos & derivados , Bradicardia/fisiopatologia , Fármacos Cardiovasculares/uso terapêutico , Clonidina/análogos & derivados , Clonidina/uso terapêutico , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacos , Angiopoietina-1/sangue , Angiopoietina-2/sangue , Animais , Bradicardia/induzido quimicamente , Fármacos Cardiovasculares/farmacologia , Clonidina/farmacologia , Vasos Coronários , Avaliação Pré-Clínica de Medicamentos , Proteínas da Matriz Extracelular/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/fisiopatologia , Ligadura , Masculino , Modelos Animais , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Volume Sistólico , Ultrassonografia , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: Coronary anomalies are frequently associated with congenital cardiac defects. Accordingly, we tested the hypothesis that the development of the tunica media of coronary arteries/arterioles is compromised in mice with cardiac defects of the outflow tract (persistent truncus arteriosus, double outlet right ventricle and transposition of the great arteries) by studying hearts of G7-9 generation mice bred from mutagenized mice caused by N-ethyl-N-nitrosourea. Mice were studied at embryonic days E16.5, E17.5, and postnatal days 1 and 11. Data were based on immunohistochemistry of serial sections. RESULTS: In 21 of 24 mice with outflow tract defects, the development of smooth muscle in arteries and arterioles was retarded; most commonly arterioles had an incomplete layer of smooth muscle or in a few instances, lacked a tunica media. In this model, an absence of a coronary ostium occurred in only 2 mice, indicating that the mechanisms underlying the formation of coronary ostia and the recruitment and differentiation of vascular smooth muscle differ. Coronary fistulas were present in 20% and dilated vessels in 30% of the hearts with cardiac defects. CONCLUSIONS: The data suggest that vascular smooth muscle recruitment and differentiation are not necessarily linked to other coronary anomalies, such as absence of a main coronary artery or branching patterns.
Assuntos
Anomalias dos Vasos Coronários/patologia , Músculo Liso Vascular/patologia , Túnica Média/patologia , Animais , Animais Recém-Nascidos , Cardiopatias Congênitas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: A large myocardial infarction (MI) initiates progressive cardiac remodeling that leads to systolic heart failure (HF). Long-term heart rate reduction (HRR) induced by the I f current inhibitor ivabradine (IVA) ameliorates left ventricular (LV) remodeling and improves systolic performance in young post-MI rats. However, the beneficial effects of chronic IVA treatment in middle-aged rats remain to be determined. METHODS: A large MI was induced in 12-month-old rats by left coronary artery ligation. Rats were treated with IVA via osmotic pumps intraperitoneal in a dose of 10.5 mg/kg/d (MI + IVA) and compared with MI and sham-operated animals 12 weeks after MI. RESULTS: Heart rate in MI + IVA rats was on average 29% lower than that of rats in the MI group. Left ventricular remodeling was comparable between post-MI groups, although MI + IVA rats did not show the compensatory thickening of the noninfarcted myocardium. Chronic HRR had no effect on transverse cardiac myocyte size and capillary growth, but it reduced the collagen content in noninfarcted myocardium. Left ventricular systolic performance remained similarly impaired in MI and MI + IVA rats. Moreover, abrupt IVA withdrawal led to worsening HF and reduction of coronary reserve. CONCLUSION: Our data reveal that chronic IVA-induced HRR does not provide sustainable benefits for LV systolic performance in middle-aged rats with post-MI HF.
Assuntos
Benzazepinas/uso terapêutico , Canais de Cátion Regulados por Nucleotídeos Cíclicos/antagonistas & inibidores , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Infarto do Miocárdio/complicações , Sístole/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Envelhecimento , Animais , Colágeno/análise , Vasos Coronários/efeitos dos fármacos , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Ivabradina , Masculino , Ratos , Ratos Sprague-Dawley , Função Ventricular EsquerdaRESUMO
The development of the heart is closely linked to its temporally and spatially regulated vascularization. Hypoxia has been shown to stimulate myocardial capillary growth and improve myocardial perfusion during reperfusion in postnatal animals exposed to chronic or intermittent exposure to hypobaria. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia via HIF-1alpha, and these two molecules are colocalized with presumptive regions of hypoxia. VEGF up-regulation in embryonic and fetal hearts correlates with vascular tube formation which progresses from an epicardial to endocardial direction prior to the establishment of a functional coronary circulation. Our studies on explanted embryonic quail hearts indicate that vascular tube formation is enhanced by hypoxia (5-10% O2) and inhibited by hyperoxia. Three splice variants of VEGF (122, 126, 190) were found to increase and decrease with hypoxia and hyperoxia, respectively. While VEGF synthesis is stimulated by hypoxia, there are differences in the vascular patterning between exogenous VEGF-induced vascularization and that induced by hypoxia. Thus, other, yet to be identified, molecules are recruited by hypoxia. Acute hypoxia selectively enhances at least three splice variants of VEGF-A, and also selectively up-regulates VEGFR-1 (flt-1). However, we suggest that VEGF-B, a ligand for VEGFR-1 may contribute to embryonic myocardial vascularization, since we have shown that it plays a key role in this process under normoxic conditions. A second mechanism by which hypoxia may play a role in vascularization of the heart is via its vasodilatory effects, once the coronary circulation is functional. Increased blood flow serves as a mechanical (stretch) trigger for activation of VEGF and its receptors. In sum, there is evidence that a relative hypoxia provides both metabolic and mechanical stimuli for vascular growth in the developing heart.
Assuntos
Coração/embriologia , Hipóxia/embriologia , Processamento Alternativo , Altitude , Animais , Vasos Coronários/embriologia , Hipóxia/patologia , Neovascularização Fisiológica , Codorniz , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
This communication briefly reviews the role of angiogenic growth factors in myocardial vessel formation during development. The earliest signs of vascularization are the migration and differentiation of angioblasts from the epicardium and subepicardium into the myocardium. A regulator of this process is vascular endothelial growth factor (VEGF), which is probably triggered by hypoxia. The subsequent formation of vascular tubes is regulated by multiple growth factors: VEGF family members, fibroblast growth factors (FGFs), and angiopoietins and their receptors. Our studies on explanted quail hearts reveal that these growth factors are interdependent. We also have shown that a harmonic interplay of growth factors characterizes early postnatal development in rats. Neutralizing antibodies to either basic FGF (bFGF) or VEGF inhibit capillary formation, whereas arteriolar growth is markedly inhibited by bFGF, but not VEGF, neutralizing antibodies. Arteriolar diameter is also increased when anti-bFGF and anti-VEGF are administered in combination. Thus, the hierarchical development of the arteriolar vasculature depends on both of these growth factors; however, the establishment of arterioles, as reflected by length density, is dependent on bFGF but not on VEG. Finally, stretch of cardiac myocytes and endothelial cells serves as a stimulus for increases in growth factor and receptor proteins. We have shown that cyclic stretch of either cell type increases VEGF, and that endothelial cells respond to stretch by up-regulation of VEGF receptor-2 (VEGFR-2), and Tie-2 receptor. These results indicate that both mechanical and metabolic factors are primary stimuli for coronary angiogenesis.
Assuntos
Anomalias dos Vasos Coronários/patologia , Anomalias dos Vasos Coronários/fisiopatologia , Substâncias de Crescimento/fisiologia , Animais , Anomalias dos Vasos Coronários/embriologia , Humanos , Ratos , Receptores de Fatores de Crescimento/fisiologiaRESUMO
BACKGROUND: An increasing body of evidence indicates that left ventricular (LV) remodeling, especially the degree of reactive myocardial hypertrophy after myocardial infarction (MI), differs in males and females. Surprisingly, to date, the sex-specific post-MI alterations of the coronary vasculature remain undetermined. Therefore, we tested the hypothesis that adaptive coronary arteriolar and capillary modifications occurring in response to reactive myocyte hypertrophy differ between middle-aged male and female post-MI rats. METHODS: A large MI was induced in 12-month-old male (M-MI) and female (F-MI) Sprague-Dawley rats by ligation of the left coronary artery. Four weeks after surgery, rats with transmural infarctions, greater than 50% of the LV free wall (FW), were evaluated. Sham-operated male (M-Sham) and female (F-Sham) rats served as an age-matched controls. RESULTS: F-MI and M-MI rats had similar sized infarcts (61.3% ± 3.9% vs. 61.5% ± 1.2%) and scale of LV remodeling, as indicated analogous remodeling indices (1.41 ± 0.11 vs. 1.39 ± 0.09). The degree of reactive post-MI myocardial hypertrophy was adequate to normalize LV weight-to-body weight ratio in both sexes; however, the F-MI rats, in contrast to males, showed no myocyte enlargement in the LVFW epimyocardium. At the same time, a greater than 50% expansion of myocyte area in the male epimyocardium and in the female endomyocardium was accompanied by a 23% (P < 0.05) increase in capillary-to-myocyte ratio, indicative of adaptive angiogenesis. Based on arteriolar length density in post-MI hearts, the resistance vessels grew in the male LVFW as well as the septum by 24% and 29%, respectively. In contrast, in females, a significant (30%) expansion of arteriolar bed was limited only to the LVFW. Moreover, in F-MI rats, the enlargement of the arteriolar bed occurred predominantly in the vessels with diameters <30 µm, whereas in M-MI rats, a substantial (two- to threefold) increase in the density of larger arterioles (30 to 50 µm in diameter) was also documented. CONCLUSION: Our data reveal that while both sexes have a relatively similar pattern of global LV remodeling and adaptive angiogenesis in response to a large MI, male and female middle-aged rats differ markedly in the regional scale of reactive cardiac myocyte hypertrophy and adaptive arteriogenesis.
RESUMO
The present study was designed to determine whether the structural composition of the scar in middle-aged post-myocardial infraction (MI) rats is affected by the biological sex of the animals. A large MI was induced in 12-month-old male (M-MI) and female (F-MI) Sprague-Dawley rats by ligation of the left coronary artery. Four weeks after the MI, rats with transmural infarctions, greater than 50% of the left ventricular (LV) free wall, were evaluated. The extent of LV remodeling and fractional volumes of fibrillar collagen (FC), myofibroblasts, vascular smooth muscle (SM) cells, and surviving cardiac myocytes (CM) in the scars were compared between the two sexes. The left ventricle of post-MI male and female rats underwent a similar degree of remodeling as evidenced by the analogous scar thinning ratio (0.46 ± 0.02 vs. 0.42 ± 0.05) and infarct expansion index (1.06 ± 0.07 vs. 1.12 ± 0.08), respectively. Most important, the contents of major structural components of the scar revealed no evident difference between M-MI and F-MI rats (interstitial FC, 80.74 ± 2.08 vs. 82.57 ± 4.53; myofibroblasts, 9.59 ± 1.68 vs.9.56 ± 1.15; vascular SM cells, 2.27 ± 0.51 vs. 3.38 ± 0.47; and surviving CM, 3.26 ± 0.39 vs. 3.05 ± 0.38, respectively). Our data are the first to demonstrate that biological sex does not influence the structural composition of a mature scar in middle-aged post-MI rats.
Assuntos
Cicatriz/patologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Fatores Etários , Animais , Feminino , Imuno-Histoquímica , Masculino , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Remodelação VentricularRESUMO
Chronic heart rate reduction (HRR) therapy following myocardial infarction, using either the pure HRR agent ivabradine or the beta-blocker atenolol, has been shown to preserve maximal coronary perfusion, via reduction of perivascular collagen and a decrease in renin-angiotensin system activation. In addition ivabradine, but not atenolol, treatment attenuated the decline in ejection fraction and decreased left ventricular wall stress. In this study, we tested the hypothesis that cell survival within the infarct region was enhanced by these two pharmacological agents. Four weeks after ligating the left anterior descending coronary artery, the percentage of the LV that contained the infarct was similar in the untreated (MI) rats and those chronically treated with ivabradine (MI + IVA) or atenolol (MI + ATEN). However, the mean thickness (mm) of the ventricular wall containing the scar was significantly greater in the MI + IVA, 1.54 (P < or = 0.01) and the MI + ATEN 1.32, compared to 1.1 in the MI group, due to a 2-fold greater area of surviving cardiomyocytes (P < or = 0.01) in the treated rats compared to the untreated group. Regions of cell survival were usually in the subepicardium, with cardiomyocytes surrounding veins or venules. However, some hearts displayed surviving cells along the endocardium. These data suggest that HRR by either ivabradine or atenolol facilitates a more favorable O2 microenvironment via improved venous flow and decreased O2 demand. We conclude that chronic HRR by these agents may serve to limit infarct expansion and wall thinning and may serve to reduce the potential for ventricular rupture.
Assuntos
Atenolol/farmacologia , Benzazepinas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Atenolol/uso terapêutico , Benzazepinas/uso terapêutico , Bradicardia/induzido quimicamente , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Cicatriz/tratamento farmacológico , Cicatriz/fisiopatologia , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Diástole/efeitos dos fármacos , Diástole/fisiologia , Modelos Animais de Doenças , Frequência Cardíaca/fisiologia , Ivabradina , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Resultado do TratamentoRESUMO
BACKGROUND: Placenta growth factor (PlGF) plays an important role in pathologic angiogenesis and is believed to be an independent biomarker in patients with coronary artery disease. However, little is known regarding the regulation of PlGF expression in heart tissue. METHODS: We determined expression changes in PlGF and its receptor, VEGFR1, in normal and abnormal biopsies from human cardiac allografts and in cardiomyocytes cultured under hypoxia or cyclical stretch conditions. RESULTS: Human donor myocardium and biopsies from allografts without fibrin deposits expressed PlGF and VEGFR1 mRNA. Biopsies (n = 7) with myocardial fibrin, elevated serum cardiac troponin I titers (p < 0.03) and cellular infiltrates (p < 0.05) expressed 1.6-fold more PlGF mRNA than biopsies from allografts without fibrin (n = 11; p < 0.05). PlGF protein was localized in cardiomyocytes, extracellular matrix and some microvessels in areas with fibrin deposition. VEGFR1 mRNA expression was not different between groups. Cultured neonatal rat cardiomyocytes constitutively expressed PlGF/VEGFR1 under normoxia. PlGF expression was increased 3.88 +/- 0.62-fold after 12 hours (n = 6; p = 0.05) and 3.64 +/- 0.41-fold after 24 hours of hypoxia (n = 6; p Assuntos
Hipóxia Celular/fisiologia
, Coração/fisiologia
, Hipóxia/fisiopatologia
, Miócitos Cardíacos/fisiologia
, Proteínas da Gravidez/genética
, Animais
, Animais Recém-Nascidos
, Biópsia
, Células Cultivadas
, Primers do DNA
, Transplante de Coração/patologia
, Transplante de Coração/fisiologia
, Humanos
, Miócitos Cardíacos/citologia
, Neovascularização Patológica/fisiopatologia
, Fator de Crescimento Placentário
, RNA Mensageiro/genética
, Ratos
, Reação em Cadeia da Polimerase Via Transcriptase Reversa
, Doadores de Tecidos
, Transplante Homólogo
, Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética