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1.
Angiogenesis ; 21(3): 557-569, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29516292

RESUMEN

The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-ß (Aß) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aß in the hind limb; thus, circulating Aß is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-ß1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.


Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Miembro Posterior/fisiopatología , Isquemia/fisiopatología , Enfermedades Vasculares Periféricas/fisiopatología , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Arteriolas/metabolismo , Arteriolas/fisiopatología , Capilares/metabolismo , Capilares/fisiopatología , Modelos Animales de Enfermedad , Endotelina-1/sangre , Arteria Femoral/metabolismo , Arteria Femoral/fisiopatología , Miembro Posterior/irrigación sanguínea , Humanos , Isquemia/genética , Ratones , Ratones Transgénicos , Microcirculación/genética , Óxido Nítrico/sangre , Enfermedades Vasculares Periféricas/sangre , Enfermedades Vasculares Periféricas/genética , Factor de Crecimiento Placentario/sangre , Factor de Crecimiento Transformador beta1/sangre
2.
J Neurosci Res ; 93(9): 1451-61, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25944265

RESUMEN

Neuropathy is the most common complication of the peripheral nervous system during the progression of diabetes. The pathophysiology is unclear but may involve microangiopathy, reduced endoneurial blood flow, and tissue ischemia. We used a mouse model of type 1 diabetes to study parallel alterations of nerves and microvessels following tissue ischemia. We designed an easily reproducible model of ischemic neuropathy induced by irreversible ligation of the femoral artery. We studied the evolution of behavioral function, epineurial and endoneurial vessel impairment, and large nerve myelinated fiber as well as small cutaneous unmyelinated fiber impairment for 1 month following the onset of ischemia. We observed a more severe hindlimb dysfunction and delayed recovery in diabetic animals. This was associated with reduced density of large arteries in the hindlimb and reduced sciatic nerve epineurial blood flow. A reduction in sciatic nerve endoneurial capillary density was also observed, associated with a reduction in small unmyelinated epidermal fiber number and large myelinated sciatic nerve fiber dysfunction. Moreover, vascular recovery was delayed, and nerve dysfunction was still present in diabetic animals at day 28. This easily reproducible model provides clear insight into the evolution over time of the impact of ischemia on nerve and microvessel homeostasis in the setting of diabetes. © 2015 Wiley Periodicals, Inc.


Asunto(s)
Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Arteria Femoral/fisiopatología , Recuperación de la Función/fisiología , Nervio Ciático/fisiopatología , Enfermedades Vasculares/fisiopatología , Análisis de Varianza , Angiografía , Animales , Antibióticos Antineoplásicos/toxicidad , Diabetes Mellitus Experimental/inducido químicamente , Modelos Animales de Enfermedad , Miembro Posterior/fisiopatología , Flujometría por Láser-Doppler , Ligadura/efectos adversos , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Conducción Nerviosa/fisiología , Lectinas de Plantas/metabolismo , Nervio Ciático/irrigación sanguínea , Nervio Ciático/patología , Estreptozocina/toxicidad , Factores de Tiempo , Enfermedades Vasculares/etiología
3.
Cell Rep ; 38(5): 110309, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35108537

RESUMEN

Peripheral artery disease (PAD) leads to considerable morbidity, yet strategies for therapeutic angiogenesis fall short of being impactful. Inflammatory macrophage subsets play an important role in orchestrating post-developmental angiogenesis, but the underlying mechanisms are unclear. Here, we find that macrophage VEGF-A expression is dependent upon the potent inflammatory cytokine, IL-1ß. IL-1ß promotes pro-angiogenic VEGF-A165a isoform transcription via activation and promoter binding of STAT3 and NF-κB, as demonstrated by gene-deletion, gain-of-function, inhibition, and chromatin immunoprecipitation assays. Conversely, IL-1ß-deletion or inhibition of STAT3 or NF-κB increases anti-angiogenic VEGF-A165b isoform expression, indicating IL-1ß signaling may also direct splice variant selection. In an experimental PAD model of acute limb ischemia, macrophage IL-1ß expression is required for pro-angiogenic VEGF-A expression and for VEGF-A-induced blood flow recovery via angio- or arteriogenesis. Though further study is needed, macrophage IL-1ß-dependent transcription of VEGF-A via STAT3 and NF-κB may have potential to therapeutically promote angiogenesis in the setting of PAD.


Asunto(s)
Interleucina-1beta/metabolismo , Macrófagos/metabolismo , FN-kappa B/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Citocinas/metabolismo , Proteínas de Unión al ADN/metabolismo , Interleucina-1beta/genética , Ratones Transgénicos , Regiones Promotoras Genéticas/genética , Factor de Transcripción STAT3/genética , Transactivadores/metabolismo
4.
J Alzheimers Dis Rep ; 5(1): 337-343, 2021 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-34113789

RESUMEN

BACKGROUND: While an association between atherosclerosis and dementia has been identified, few studies have assessed the longitudinal relationship between aortic valve calcification (AVC) and cognitive impairment (CI). OBJECTIVE: We sought to determine whether AVC derived from lung cancer screening CT (LCSCT) was associated with CI in a moderate-to-high atherosclerotic risk cohort. METHODS: This was a single site, retrospective analysis of 1401 U.S. veterans (65 years [IQI: 61, 68] years; 97%male) who underwent quantification of AVC from LCSCT indicated for smoking history. The primary outcome was new diagnosis of CI identified by objective testing (Mini-Mental Status Exam or Montreal Cognitive Assessment) or by ICD coding. Time-to-event analysis was carried out using AVC as a continuous variable. RESULTS: Over 5 years, 110 patients (8%) were diagnosed with CI. AVC was associated with new diagnosis of CI using 3 Models for adjustment: 1) age (HR: 1.104; CI: 1.023-1.191; p = 0.011); 2) Model 1 plus hypertension, hyperlipidemia, diabetes, CKD stage 3 or higher (glomerular filtration rate < 60 mL/min) and CAD (HR: 1.097; CI: 1.014-1.186; p = 0.020); and 3) Model 2 plus CVA (HR: 1.094; CI: 1.011-1.182; p = 0.024). Sensitivity analysis demonstrated that the association between AVC and new diagnosis of CI remained significant upon exclusion of severe AVC (HR: 1.100 [1.013-1.194]; p = 0.023). Subgroup analysis demonstrated that this association remained significant when including education in the multivariate analysis (HR: 1.127 [1.030-1.233]; p = 0.009). CONCLUSION: This is the first study demonstrating that among mostly male individuals who underwent LCSCT, quantified aortic valve calcification is associated with new diagnosis of CI.

5.
Diabetes ; 61(10): 2621-32, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22596048

RESUMEN

We hypothesized that in vitro treatment of peripheral blood mononuclear cells (PB-MNCs) from diabetic patients with ephrin-B2/Fc (EFNB2) improves their proangiogenic therapeutic potential in diabetic ischemic experimental models. Diabetes was induced in nude athymic mice by streptozotocin injections. At 9 weeks after hyperglycemia, 10(5) PB-MNCs from diabetic patients, pretreated by EFNB2, were intravenously injected in diabetic mice with hindlimb ischemia. Two weeks later, the postischemic neovascularization was evaluated. The mechanisms involved were investigated by flow cytometry analysis and in vitro cell biological assays. Paw skin blood flow, angiographic score, and capillary density were significantly increased in ischemic leg of diabetic mice receiving EFNB2-activated diabetic PB-MNCs versus those receiving nontreated diabetic PB-MNCs. EFNB2 bound to PB-MNCs and increased the adhesion and transmigration of PB-MNCs. Finally, EFNB2-activated PB-MNCs raised the number of circulating vascular progenitor cells in diabetic nude mice and increased the ability of endogenous bone marrow MNCs to differentiate into cells with endothelial phenotype and enhanced their proangiogenic potential. Therefore, EFNB2 treatment of PB-MNCs abrogates the diabetes-induced stem/progenitor cell dysfunction and opens a new avenue for the clinical development of an innovative and accessible strategy in diabetic patients with critical ischemic diseases.


Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Tipo 2/fisiopatología , Efrina-B2/farmacología , Isquemia/terapia , Leucocitos Mononucleares/efectos de los fármacos , Neovascularización Patológica/fisiopatología , Neovascularización Fisiológica/efectos de los fármacos , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Miembro Posterior/irrigación sanguínea , Miembro Posterior/fisiopatología , Humanos , Isquemia/metabolismo , Isquemia/fisiopatología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/trasplante , Masculino , Ratones , Ratones Desnudos , Neovascularización Patológica/metabolismo , Neovascularización Fisiológica/fisiología
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