β3 integrin deficiency promotes atherosclerosis and pulmonary  inflammation in high-fat-fed, hyperlipidemic mice

Weng, Sherry; Zemany, Laura; Standley, Kara N.; Novack, Deborah V.; Regina, Marie La; Bernal‐Mizrachi, Carlos; Coleman, Trey; Semenkovich, Clay F.

doi:10.1073/pnas.1137612100

Cited by 74 publications

(53 citation statements)

References 58 publications

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“…28 However, recent data have challenged the original view that ␣ v ␤ 3 plays a major role in pathophysiological angiogenesis and suggest that this integrin may in fact suppress neovascularization. 29 Because ␤ 3 deficiency increases atherosclerosis in the LDL receptor Ϫ/Ϫ mouse, 30 this may nevertheless be consistent with a role of angiogenesis in the development of atherosclerosis.…”

Section: Angiogenesis and Atherosclerosismentioning

confidence: 77%

Role of Angiogenesis in Cardiovascular Disease

et al. 2005

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Abstract-The role of angiogenesis in atherosclerosis and other cardiovascular diseases has emerged as a major unresolved issue. Angiogenesis has attracted interest from opposite perspectives. Angiogenic cytokine therapy has been widely regarded as an attractive approach both for treating ischemic heart disease and for enhancing arterioprotective functions of the endothelium; conversely, a variety of studies suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Here, we critically review the evidence supporting a role for angiogenesis and angiogenic factors in atherosclerosis and neointima formation, emphasizing the problems raised by some of the landmark studies and the suitability of animal models of atherosclerosis and neointimal thickening for investigating the role of angiogenesis. Because many of the relevant studies have focused on the role of vascular endothelial growth factor (VEGF), we consider this work in the wider context of VEGF biology and in light of recent experience from clinical trials of VEGF and other angiogenic cytokines for ischemic heart disease. Also discussed are recent findings suggesting that, although angiogenesis may contribute to neointimal growth, it is not required for the initiation of intimal thickening. Our assessment of the evidence leads us to conclude that, although microvessels are a feature of advanced human atherosclerotic plaques, it remains unclear whether angiogenesis either plays a central role in the development of atherosclerosis or is responsible for plaque instability. Furthermore, current evidence from clinical trials of both proangiogenic and antiangiogenic therapies does not suggest that inhibition of angiogenesis is likely to be a viable therapeutic strategy for cardiovascular disease.

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Section: Angiogenesis and Atherosclerosismentioning

confidence: 77%

Role of Angiogenesis in Cardiovascular Disease

et al. 2005

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“…29 The ␤ 3 integrin subfamily consists of 2 integrins, GP IIb/IIIa (␣ IIb ␤ 3 ) and ␣ v ␤ 3 . GP IIb/IIIa is expressed exclusively by megakaryocytes and platelets and mediates platelet adhesion, aggregation, and activation.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, ␣ v ␤ 3 integrin is present on a variety of vascular cells, including monocytes, fibroblasts, endothelial cells, and smooth muscle cells, where it modulates multiple cellular functions, including proliferation, migration, and inflammation. 29,30 Importantly, ␤ 3 -null mutants lack both GP IIb/IIIa and ␣ v ␤ 3 , resulting in enhanced atherosclerotic lesion formation. 29 In contrast, we report here that the selective loss of platelet GP IIb/IIIa protects mice from atherosclerotic lesion formation.…”

Section: Discussionmentioning

confidence: 99%

Platelet Adhesion Via Glycoprotein IIb Integrin Is Critical for Atheroprogression and Focal Cerebral Ischemia

Maßberg¹,

Schürzinger²,

Lorenz³

et al. 2005

Circulation

138

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Background-The platelet glycoprotein (GP) IIb/IIIa integrin binds to fibrinogen and thereby mediates platelet aggregation. Here, we addressed the role of GP IIb for platelet adhesion and determined the relevance of platelet GP IIb for the processes of atherosclerosis and cerebral ischemia-reperfusion (I/R) injury. Methods and Results-GP IIbϪ/Ϫ mice were generated and bred with ApoE Ϫ/Ϫ animals to create GP IIb Ϫ/Ϫ ApoE Ϫ/Ϫ mice. Platelet adhesion to the mechanically injured or atherosclerotic vessel wall was monitored by in vivo video fluorescence microscopy. In the presence of GP IIb, vascular injury and early atherosclerosis induced platelet adhesion in the carotid artery (CA). In contrast, platelet adhesion was significantly reduced in the absence of GP IIb integrin (PϽ0.05). To address the contribution of platelet GP IIb to atheroprogression, we determined atherosclerotic lesion formation in the CA and aortic arch (AA) of GP IIb ϩ/ϩ ApoE Ϫ/Ϫ or GP IIb Ϫ/Ϫ ApoE Ϫ/Ϫ mice. Interestingly, the absence of GP IIb attenuated lesion formation in CA and AA, indicating that platelets, via GP IIb, contribute substantially to atherosclerosis. Next, we assessed the implication of GP IIb for cerebral I/R injury. We observed that after occlusion of the middle cerebral artery, the cerebral infarct size was drastically reduced in mice lacking GP IIb compared with wild-types. Conclusions-These findings show for the first time in vivo that GP IIb not only mediates platelet aggregation but also triggers platelet adhesion to exposed extracellular matrices and dysfunctional endothelial cells. In a process strictly involving GP IIb, platelets, which are among the first blood cells to arrive at the scene of endothelial dysfunction, contribute essentially to atherosclerosis and cerebral I/R injury. (Circulation. 2005;112:1180-1188.)

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“…Multiple knockouts obtained by crossing ␤3 Ϫ/Ϫ mice with apoE Ϫ/Ϫ and LDR receptor Ϫ/Ϫ mice again showed how ␤3 deficiency was associated with more atherosclerosis, whereas a high frequency of fatal pneumonitis was also noted. 92 Expression of inflammatory markers, such as CD36, CD40L, and CD40 (all known to interact with ␤3), was increased in the lung and the vessel wall and linked to the loss of a tonic suppressive effect of ␣v␤3 on diet-induced inflammatory events.…”

Section: Mouse Models With Deficiencies Of ␣Iib␤3 and ␣V␤3mentioning

confidence: 99%

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Nurden

Fiore

Pillois

2011

Blood

200

267

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Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetypeinherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, ␣IIb␤3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for ␤3 has a wide tissue distribution when present as ␣v␤3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of ␤3-deficiency or nonfunction are being increasingly described. (Blood. 2011;118(23):5996-6005) IntroductionGlanzmann thrombasthenia (GT) is the most frequently encountered inherited disorder of platelet function. [1][2][3] Patients have a lifelong hemorrhagic syndrome typically characterized by episodes of spontaneous mucocutaneous bleeding. Platelets fail to aggregate in response to stimuli because they lack or have nonfunctional ␣IIb␤3 integrin (formerly known as GPIIb-IIIa). Resting normal platelets are suspected to have ␣IIb␤3 in a bent conformation; when platelets are stimulated, the integrin straightens in parallel to the exposure of determinants essential for the binding of fibrinogen (Fg) or other soluble adhesive proteins. 3,4 The latter assure aggregation by cross-linking adjacent platelets, a process that cannot occur in GT. Elucidation of this pathway led to the development of integrin-blocking drugs that are strong inhibitors of arterial thrombosis, thereby increasing interest in the clinical manifestations of GT. 3,4 Platelet ␣IIb␤3 also transmits the forces generated by intracellular cytoskeletal proteins during clot contraction and platelet spreading, processes that also fail in patients lacking adequate amounts of functional integrin.Although the GT phenotype is well defined, bleeding severity differs considerably between affected persons, even within the same family or ethnic group. 1,2 In this review, we discuss phenotypic variability, present variant types, and identify possible additional effects associated with ␤3 deletion, for although ␣IIb is largely restricted to the megakaryocyte (MK) lineage, ␤3 is much more widespread in its tissue distribution occurring as ␣v␤3, the vitronectin receptor. 5,6 Data for patients will be compared with those obtained for...

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β3 integrin deficiency promotes atherosclerosis and pulmonary inflammation in high-fat-fed, hyperlipidemic mice

Cited by 74 publications

References 58 publications

Role of Angiogenesis in Cardiovascular Disease

Role of Angiogenesis in Cardiovascular Disease

Platelet Adhesion Via Glycoprotein IIb Integrin Is Critical for Atheroprogression and Focal Cerebral Ischemia

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

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