Toward the Clinical Application of Therapeutic Angiogenesis Against Pediatric Ischemic Retinopathy.

Therapeutic angiogenesis refers to strategies of inducing angiogenesis to treat diseases involving ischemic conditions. Historically, most attempts and achievements have been related to coronary and peripheral artery diseases. In this review, we propose the clinical application of therapeutic angiogenesis for the treatment of pediatric ischemic retinopathy, including retinopathy of prematurity, familial exudative retinopathy, and NDP-related retinopathy. These diseases are all characterized by the reduction of physiological angiogenesis and the following induction of pathological angiogenesis. Therapeutic angiogenesis, which supplements insufficient physiological angiogenesis, may be a therapeutic approach for ischemic conditions. Various molecules and modalities can be utilized to apply therapeutic angiogenesis for the treatment of ischemic retinopathy, as in coronary and peripheral artery diseases. Experiences with cardiovascular diseases provide a useful reference for the further clinical application of therapeutic angiogenesis in pediatric ischemic retinopathy. Recombinant proteins and gene therapy are powerful tools to deliver angiogenic factors to retinal tissues directly. Furthermore, endothelial progenitor or bone marrow-derived cells can be injected into the vitreous cavity of the eye for therapeutic angiogenesis. Intraocular injections are highly promising for the delivery of therapeutics for therapeutic angiogenesis. We expect that therapeutic angiogenesis will be a breakthrough in the treatment of pediatric ischemic retinopathy.

Evaluation of 68Ga-Glutamate Carboxypeptidase II Ligand Positron Emission Tomography for Clinical Molecular Imaging of Atherosclerotic Plaque Neovascularization.

OBJECTIVE: Intraplaque neovascularization contributes to the progression and rupture of atherosclerotic lesions. Glutamate carboxypeptidase II (GCPII) is strongly expressed by endothelial cells of tumor neovasculature and plays a major role in hypoxia-induced neovascularization in rodent models of benign diseases. We hypothesized that GCPII expression may play a role in intraplaque neovascularization and may represent a target for imaging of atherosclerotic lesions. The aim of this study was to determine frequency, pattern, and clinical correlates of vessel wall uptake of a 68Ga-GCPII ligand for positron emission tomographic imaging. APPROACH AND RESULTS: Data from 150 patients undergoing 68Ga-GCPII ligand positron emission tomography were evaluated. Tracer uptake in various arterial segments was analyzed and was compared with calcified plaque burden, cardiovascular risk factors, and immunohistochemistry of carotid specimens. Focal arterial uptake of 68Ga-GCPII ligand was identified at 5776 sites in 99.3% of patients. The prevalence of uptake sites was highest in the thoracic aorta; 18.4% of lesions with tracer uptake were colocalized with calcified plaque. High injected dose (P=0.0005) and obesity (P=0.007) were significantly associated with 68Ga-GCPII ligand accumulation, but other cardiovascular risk factors showed no association. The number of 68Ga-GCPII ligand uptake sites was significantly associated with overweight condition (P=0.0154). Immunohistochemistry did not show GCPII expression. Autoradiographic blocking studies indicated nonspecific tracer binding. CONCLUSIONS: 68Ga-GCPII ligand positron emission tomography does not identify vascular lesions associated with atherosclerotic risk. Foci of tracer accumulation are likely caused by nonspecific tracer binding and are in part noise-related. Taken together, GCPII may not be a priority target for imaging of atherosclerotic lesions.

Estrés hemodinámico inducido por ejercicio: bases fisiológicas e impacto clínico / Exercise-induced shear stress: Physiological basis and clinical impact

La regulación fisiológica de la función vascular es esencial para la salud cardiovascular y depende de un adecuado control de mecanismos moleculares desencadenados por células endoteliales en respuesta a estímulos mecánicos y químicos inducidos por flujo sanguíneo. La disfunción endotelial es uno de los principales factores de riesgo de enfermedad cardiovascular, donde un desequilibrio entre la síntesis de moléculas vasodilatadoras y vasoconstrictoras constituye uno de sus principales mecanismos. En este contexto, el estrés de flujo es uno de los estímulos más importantes para mejorar la función vascular, gracias a que la mecanotransducción endotelial generada por la estimulación de diversos mecanosensores endoteliales induce la generación de estímulos intracelulares que culmina con un incremento en la biodisponibilidad de moléculas vasodilatadoras como el óxido nítrico y, a largo plazo, con la inducción de mecanismos angiogénicos. Estos mecanismos permiten proporcionar el sustento fisiológico a los efectos del ejercicio físico sobre la salud vascular. En la presente revisión se discuten los mecanismos moleculares implicados en la respuesta vascular modulada por estrés de flujo inducido por ejercicio y su impacto en la reversión del daño vascular asociado a las enfermedades cardiovasculares más prevalentes en nuestra población.

The physiological regulation of vascular function is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the major risk factors for cardiovascular disease, where an imbalance between synthesis of vasodilator and vasoconstrictor molecules is one of its main mechanisms. In this context, the shear stress is one of the most important mechanical stimuli to improve vascular function, due to endothelial mechanotransduction, triggered by stimulation of various endothelial mechanosensors, induce signaling pathways culminating in increased bioavailability of vasodilators molecules such as nitric oxide, that finally trigger the angiogenic mechanisms. These mechanisms allow providing the physiological basis for the effects of exercise on vascular health. In this review it is discussed the molecular mechanisms involved in the vascular response induced by shear stress and its impact in reversing vascular injury associated with the most prevalent cardiovascular disease in our population.

[Exercise-induced shear stress: Physiological basis and clinical impact]. / Estrés hemodinámico inducido por ejercicio: bases fisiológicas e impacto clínico.

The physiological regulation of vascular function is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the major risk factors for cardiovascular disease, where an imbalance between synthesis of vasodilator and vasoconstrictor molecules is one of its main mechanisms. In this context, the shear stress is one of the most important mechanical stimuli to improve vascular function, due to endothelial mechanotransduction, triggered by stimulation of various endothelial mechanosensors, induce signaling pathways culminating in increased bioavailability of vasodilators molecules such as nitric oxide, that finally trigger the angiogenic mechanisms. These mechanisms allow providing the physiological basis for the effects of exercise on vascular health. In this review it is discussed the molecular mechanisms involved in the vascular response induced by shear stress and its impact in reversing vascular injury associated with the most prevalent cardiovascular disease in our population.

Biología del Desarrollo Vascular: Mecanismos en Condiciones Físiológicas y Estrés Flujo / Biology of Vascular Development: Mechanisms in Physiological Conditions and Shear Stress

La vasculogénesis es controlada por una serie de mecanismos que se activan en función del tiempo y del espacio durante el desarrollo embrionario. Múltiples son las vías de señalización implicadas en las etapas del proceso vasculogénico, las que se inician con estímulos angiogénicos desde el mesodermo o desde el endodermo para dar origen a los angioblastos (células progenitoras endoteliales). Proteínas como el factor de crecimiento vascular endotelial (VEGF), factor de crecimiento fibroblastico 2 (FGF2), entre otras, constituyen factores claves en la inducción de este proceso. Posteriormente, los angioblastos deben migrar para dar origen a los vasos primitivos, proceso en el que participan factores atrayentes y repulsivos que orientarán la dirección de su migración. Adicionalmente, los mecanismos de diferenciación arterio-venosa, regulados por la vía de señalización Hedgegog, VEGF y Notch, son determinados antes del inicio de la circulación, lo que sugiere que el destino de la célula endotelial se encuentra genéticamente determinado. Por su parte, los procesos de remodelación y proliferación vascular post natal, son generados a través de la formación de nuevos vasos a partir de vasos pre existentes (angiogénesis). El factor angiogénico que induce los cambios morfológicos y funcionales en las células endoteliales es el VEGFA, las cuales, adquieren la capacidad de direccionar al nuevo vaso en desarrollo. Uno de los principales estímulos físicos que modifica el patrón de crecimiento de los lechos vasculares es el estrés de flujo, el cual, es susceptible de ser modificado por situaciones de estrés como el ejercicio físico. En la presente revisión, se abordan los principales mecanismos implicados en la regulación fisiológica de la vasculogénesis y angiogénesis. Adicionalmente, se discutirán los mecanismos que sustentan la respuesta vascular inducida por estrés de flujo, considerando su rol en el establecimiento de los patrones de crecimiento vascular.

Vasculogenesis is controlled by a number of mechanisms that are activated as a function of time and space during embryonic development. Multiple signaling pathways are involved in the stages of vasculogenic process, which start with angiogenic stimuli from the mesoderm or the endoderm to give rise to angioblasts (endothelial progenitor cells). Proteins such as vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), among others, are key factors in the induction of this process. Subsequently, the angioblasts must migrate to give birth to primitive vessels, a process that involves attractive and repulsive factors that guide the direction of their migration. Additionally, arterial and venous differentiation regulated hedgegog signaling pathway, VEGF and Notch are determined before the start of circulation, suggesting that the endothelial cell fate is determined genetically. On the other hand, the processes of remodeling and postnatal vascular proliferation are generated through the formation of new vessels from pre-existing vessels (angiogenesis). The angiogenic factor that induces morphological and functional changes in the endothelial cells is the VEGFA, these vessels acquire the ability to address the new developing vessel. One of the main physical stimuli that modify the growth pattern of the vascular beds is the shear stress, which is modified by exercise. In this review, the main mechanisms involved in the physiological regulation of vasculogenesis and angiogenesis are addressed. Additionally, the mechanisms underlying the vascular response induced by shear stress will be discussed, considering its role in establishing patterns of vascular growth.

Effects of SDY-08 isolated from Dasyatis akajei on angiogenesis and tissue repair / 中华创伤杂志

Objective To investigate the effects of SDY-08 isolated from Dasyatis akajei on tis-sue repair. Methods MTT assay was performed to measure the effect of SDY-08 on the growth of ECV-304 cells. The effect of SDY-08 on angiogenesis was detected in the chick embryochorioallantoic membrane (CAM). Mouse wound model was applied to investigate the effect of SDY-08 on tissue repair. Immunohistochemical staining assay and Western blotting were adopted to examine the expression changes of vascular endothelial growth factor (VEGF), Bcl-2 and Bax in wound tissues in response to SDY-08. Results The proliferation rates of SDY-08 at final concentration of 80 μg/ml promoting ECV-304 cells were 28.1%, 115.6% and 81.4% respectively at 12, 24 and 36 hours. The induction rate of angiogene-sis of CAM by SDY-08 at concentration of 1.6 mg/ml was 72.1%. SDY-08 at 0.5 mg/ml markedly in-duced acceleration of wound healing in mouse model two days in advance. SDY-08 up-regulated either ex-pressions of VEGF in trauma group or that of Bcl-2 and VEGF of ECV-304 cells, but down-regulated ex-pression of Box. Conclusions SDY-08 can significantly promote angiogenesis and tissue repair, which is closely correlated with its effect of up-regulating expressions of VEGF and Bcl-2 as well with that of down-regulating expression of Box.