visualizing-membrane-ruffle-formation-using-scanning-electron

Visualizing Membrane Ruffle Formation using Scanning Electron Microscopy

Membrane ruffling is the formation of motile plasma membrane protrusions containing a meshwork of newly polymerized actin filaments. Membrane ruffles may ...

Medical College of Georgia at Augusta University

The lymphatic network is well known for its role in the maintenance of tissue fluid homeostasis, absorption of dietary lipids, trafficking of immune cells, and adaptive immunity. Aberrant lymphatic function has been linked to lymphedema and immune disorders for a long time. Discovery of lymphatic cell markers, novel insights into developmental and postnatal lymphangiogenesis, development of genetic mouse models, and the introduction of new imaging techniques have improved our understanding of lymphatic function in both health and disease, especially in the last decade. Previous studies linked the lymphatic vasculature to atherosclerosis through regulation of immune responses, reverse cholesterol transport, and inflammation. Despite extensive research, many aspects of the lymphatic circulation in atherosclerosis are still unknown and future studies are required to confirm that arterial lymphangiogenesis truly represents a therapeutic target in patients with cardiovascular disease. In this review article, we provide an overview of factors and mechanisms that regulate lymphangiogenesis, summarize recent findings on the role of lymphatics in macrophage reverse cholesterol transport, immune cell trafficking and pathogenesis of atherosclerosis, and present an overview of pharmacological and genetic strategies to modulate lymphatic vessel density in cardiovascular tissue.

Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges.

Copper (Cu) is essential micronutrient, and its dysregulation is implicated in aortic aneurysm (AA) development. The Cu exporter ATP7A (copper-transporting P-type ATPase/Menkes ATPase) delivers Cu via the Cu chaperone Atox1 (antioxidant 1) to secretory Cu enzymes, such as lysyl oxidase, and excludes excess Cu. Lysyl oxidase is shown to protect against AA formation. However, the role and mechanism of ATP7A in AA pathogenesis remain unknown. Approach and Results: Here, we show that Cu chelator markedly inhibited Ang II (angiotensin II)-induced abdominal AA (AAA) in which ATP7A expression was markedly downregulated. Transgenic ATP7A overexpression prevented Ang II-induced AAA formation. Conversely, Cu transport dysfunctional ATP7A/ApoE mice exhibited robust AAA formation and dissection, excess aortic Cu accumulation as assessed by X-ray fluorescence microscopy, and reduced lysyl oxidase activity. In contrast, AAA formation was not observed in Atox1/ApoE mice, suggesting that decreased lysyl oxidase activity, which depends on both ATP7A and Atox1, was not sufficient to develop AAA. Bone marrow transplantation suggested importance of ATP7A in vascular cells, not bone marrow cells, in AAA development. MicroRNA (miR) array identified miR-125b as a highly upregulated miR in AAA from ATP7A/ApoE mice. Furthermore, miR-125b target genes (histone methyltransferase Suv39h1 and the NF-κB negative regulator TNFAIP3 [tumor necrosis factor alpha induced protein 3]) were downregulated, which resulted in increased proinflammatory cytokine expression, aortic macrophage recruitment, MMP (matrix metalloproteinase)-2/9 activity, elastin fragmentation, and vascular smooth muscle cell loss in ATP7A/ApoE mice and reversed by locked nucleic acid-anti-miR-125b infusion.

Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b.

Impaired lymphatic drainage of the arterial wall results in intimal lipid accumulation and atherosclerosis. However, the mechanisms regulating lymphangiogenesis in atherosclerotic arteries are not well understood. Our studies identified elevated levels of matrix protein R-spondin 2 (RSPO2) in atherosclerotic arteries. In this study, we investigated the role of RSPO2 in lymphangiogenesis, arterial cholesterol efflux into lesion-draining lymph nodes (LNs) and development of atherosclerosis.

Article	Year
Arterial Lymphatics in Atherosclerosis: Old Questions, New Insights, and Remaining Challenges. Journal of clinical medicine\| PubMed ID: 30979062	2019
Copper Transporter ATP7A (Copper-Transporting P-Type ATPase/Menkes ATPase) Limits Vascular Inflammation and Aortic Aneurysm Development: Role of MicroRNA-125b. Arteriosclerosis, thrombosis, and vascular biology\| PubMed ID: 31554420	2019
Role of R-spondin 2 in arterial lymphangiogenesis and atherosclerosis. Cardiovascular research\| PubMed ID: 32750106	2021

Bhupesh Singla

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