Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Ashoff, Astrid; Qadri, Fatimunnisa; Eggers, Reinhard; Raasch, Walter; Dendorfer, Andreas

doi:10.1159/000335214

Cited by 15 publications

(14 citation statements)

References 72 publications

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“…Interestingly, both metformin and rosiglitazone were comparably effective in improving glycemic control, reducing plasma levels of nitrotyrosine and in blunting the loss in MVD. This is an observation that is consistent with those from previous studies in both relevant animal models [2,6] and in human subjects afflicted with diabetes mellitus [17,18], where superior maintenance of insulin sensitivity and glycemic control where key variables associated with improving MVD (where rarefaction had occurred) and attenuating its loss (where rarefaction was relatively mild).…”

Section: Discussionsupporting

confidence: 91%

Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability

et al. 2015

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Objective Chronic presentation of the metabolic syndrome (MS) is associated with an increased likelihood for stroke and poor stroke outcomes following occlusive cerebrovascular events. However, the physiological mechanisms contributing to compromised outcomes remain unclear, and the degree of cerebral cortical microvascular density (MVD) may represent a central determinant of stroke outcomes. Methods This study used the obese Zucker rat (OZR) model of MS and clinically-relevant, chronic interventions to determine the impact on cerebral cortical microvascular rarefaction via immunohistochemistry with a parallel determination of cerebrovascular function to identify putative mechanistic contributors. Results OZR exhibited a progressive rarefaction (to ~80% control MVD) of the cortical microvascular networks vs. lean Zucker rats. Chronic treatment with anti-hypertensive agents (captopril/hydralazine) had limited effectiveness in blunting rarefaction, although treatments improving glycemic control (metformin/rosiglitazone) were superior, maintaining ~94% control MVD. Chronic treatment with the antioxidant TEMPOL severely blunted rarefaction in OZR, although this ameliorative effect was prevented by concurrent NOS inhibition. Conclusions Further analyses revealed that the maintenance of glycemic control and vascular nitric oxide bioavailability were stronger predictors of cerebral cortical MVD in OZR than was prevention of hypertension, and this may have implications for chronic treatment of CVD risk under stroke-prone conditions.

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Section: Discussionsupporting

confidence: 91%

Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability

et al. 2015

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“…There are discrepancies between papers describing either proangiogenic [ 5 , 20 - 22 , 32 ], antiangiogenic [ 27 , 28 , 33 - 35 ] or biphasic [ 36 ] effects of PPARγ agonists. Therefore we checked whether impaired angiogenic potential of PACs isolated from db/db mice can be corrected by rosiglitazone.…”

Section: Resultsmentioning

confidence: 99%

“…It has been demonstrated that PPARγ ligands influence angiogenesis, acting generally as proangiogenic agents, and increasing number of bone marrow derived endothelial progenitors. In animal models, such as diabetic rats, treatment with pioglitazone increased density of capillaries in the heart and skeletal muscle by a mechanism unrelated to VEGF-mediated angiogenesis [ 5 ]. Proangiogenic effect of pioglitazone, associated with accelerated healing of ulcers, was also observed in normoglycemic rats [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Diabetes, due to hyperglycemia and insulin resistance, is associated with poor outcomes due to endothelial dysfunction and impaired angiogenesis, followed by vascular occlusive events, decreased vascular density in ischemic tissues, and delayed wound healing [ 4 , 5 ]. Proper vascular repair and angiogenesis depend both on mature endothelial cells and endothelial progenitors [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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PPARγ activation but not PPARγ haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors

Kotlinowski¹,

Grochot-Przęczek²,

Taha³

et al. 2014

Cardiovasc Diabetol

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BackgroundPeroxisome proliferator-activated receptor-γ (PPARγ) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPARγ on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs).MethodsPACs were isolated from bone marrow of 10–12 weeks old, wild type, db/db and PPARγ heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 μmol/L) or GW9662 (10 μmol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model.ResultsECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPARγ activator). Correction of diabetes by administration of rosiglitazone in vivo did not improve angiogenic potential of isolated PACs or ECs. In a hind limb ischemia model we demonstrated that local injection of conditioned media harvested from wild type PACs improved the blood flow restoration in db/db mice, confirming the importance of paracrine action of the bone marrow-derived cells.Transcriptome analysis showed an upregulation of prooxidative and proinflammatory pathways, and downregulation of several proangiogenic genes in db/db PACs. Interestingly, db/db PACs had also a decreased level of PPARγ and changed expression of PPARγ-regulated genes. Using normoglycemic PPARγ+/− mice we demonstrated that reduced expression of PPARγ does not influence neovascularization either in wound healing or in hind limb ischemia models.ConclusionsIn summary, activation of PPARγ by rosiglitazone improves angiogenic potential of diabetic ECs and PACs, but decreased expression of PPARγ in diabetes does not impair angiogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-014-0150-7) contains supplementary material, which is available to authorized users.

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“…This workflow is associated with procedural risks, reduction of patient quality of life, exposure to ionizing radiation, and high costs . Few studies have specifically addressed CMD treatment, despite the fact that several drugs proved effective in restoring microvascular function in animal models of MD . This in part reflects the absence of a single tool for the diagnosis of CMD and to monitor effects of therapy.…”

Section: Functional Assessment Of the Coronary Microcirculationmentioning

confidence: 99%

Current perspectives in coronary microvascular dysfunction

et al. 2017

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The coronary arterial system consists of large epicardial coronary arteries, pre-arterioles, and arterioles, which together closely regulate CBF. Structural, functional, and extravascular abnormalities of the microcirculation lead to CMD. CMD can present with symptoms suggestive of CAD, often in the absence of significant obstructive epicardial CAD. Conventional invasive angiography does not allow direct visualization of the microcirculation. Invasive indices, such as CBF and CFR, and non-invasive imaging modalities, such as CMR and PET, can be used to quantify absolute MBF and enable a direct and accurate assessment of coronary microvascular function. CMD appears to be more prevalent in women, typically presenting with symptoms of ischemia with unobstructed coronary arteries, and has a relatively unfavorable prognosis. CMD is classified clinically depending on the presence or absence of epicardial CAD, myocardial disease, or iatrogenic causes. Although invasive intracoronary techniques can be used to detect CMD, these cannot provide insight into the mechanisms involved in its pathogenesis. Imaging modalities such as CMR and cardiac PET are becoming indispensable tools in the evaluation of suspected CMD.

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Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Cited by 15 publications

References 72 publications

Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability

Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability

PPARγ activation but not PPARγ haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors

Current perspectives in coronary microvascular dysfunction

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