Cardiovascular Diseases; Cell Membrane Permeability; Circulatory and Respiratory Physiological Phenomena; Neoplasms; Chemicals and Drugs
Skin Diseases Research Center, Yale
The vascular endothelium lines all the blood vessels found in higher organisms and as such is the largest endocrine organ of the body. Proteins, lipids and the gas, nitric oxide, produced by the endothelium protect blood vessels from environmental stress, oxidative damage and thrombosis which in turn maintains the patency of blood vessels and ensures the precise delivery of nutrients and oxygen to tissues. In most cardiovascular diseases, diabetes, as well as in cancer, dysregulation of the vascular endothelium contributes directly to disease progression. Thus, our lab is generally interested in what etiologic factors or genes regulate the transition of a healthy "normal" endothelium to a a lab we integrate molecules to disease, and use a broad range of technologies and strategies to achieve our goals.
A newly emerging theme in the lab is using proteomics to discover novel proteins that may regulate blood vessel function. We have isolated caveolae from endothelial cells in culture and have identified several new proteins. As an example, we have identified Nogo-B which had no known function. Nogo-B is a member of the reticulon family of proteins including Nogo-A and -C. Nogo-A produced in oligodendrocytes has been identified as an inhibitor of axonal growth and repair. We discovered that Nogo-B promotes the adhesion of endothelial cells and smooth muscle cells and is a potent chemoattractant for endothelial cells. In contrast to its motogenic properties in the endothelium, Nogo-B blocks PDGF mediated migration of smooth muscle cells.
Extensive Research Description
The vascular endothelium is the largest endocrine organ in the body, at the interface of blood and tissue. As such, many common diseases such as atherosclerosis, heart disease, cancer, macular degeneration and diabetes have a common signature of endothelial cell dysfunction. Our laboratory is focused on understanding the etiology of vascular dysfunction in these diseases and is focused on several broad aspects of endothelial cell biology and function.
We are exploring multiple avenues of research with a critical eye towards discovering new, biologically relevant therapeutic targets and pathways.
1. Elucidation how endothelial NOS (eNOS) is regulated in the context of normal physiology and in disease using cellular and molecular approaches in signal transduction. Particular areas are the study of cholesterol enriched plasmalemmal microdomains, caveolins, cavins, and downstream pathways.
2. Examination of VEGF signaling in the context of physiological and pathophysiologal angiogenesis with specific emphasis on the protein kinase Akt in genetic mouse models;
3, miRNA regulation of endothelial cell and smooth muscle cell differentiation;
4. Proteomic analysis of protein palmitoylation and phosphorylation;
5. Nogo-B (reticulon 4B)/NgBR structure function and cellular biology in cholesterol metabolism and protein N-glycosylation;
We typically use basic molecular and cellular approaches and apply our findings to complex genetic systems (compound mutant mouse strains) to study blood vessel structure and function in physiology and disease.- Cell biology of Nogo and Nogo receptors
- miRNAs in cancer and angiogenesis
- NO signaling
- Regulation of plasma membrane microdomains and cardiovascular function
- Vascular mechanisms of atherosclerosis
- Harrison, K.D., Miao, R.Q., Fernandez-Hernando, C., Suarez, Y., Davalos, A. and Sessa, W.C. Nogo-B receptor stabilizes Nieman Pick Type C2 protein and regulate intracellular cholesterol trafficking. Cell Metabolism, 10: 208-218 (2009).
- Schleicher, M., Yu, J., Murata, T., Derakhshan, B., Atochin, D., Qian, L., Kashiwagi, S., Di Lorenzo, A., Harrison, K.D., Huang, P.L and Sessa, W.C. The Akt1-eNOS axis illustrates the specificity of kinase-substrate relationships in vivo. Science Signaling, 2(82):ra41 (2009).
- Suárez Y, Fernández-Hernando C, Yu J, Gerber SA, Harrison KD, Pober JS, Iruela-Arispe ML, Merkenschlager M and Sessa WC. Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci U S A. 16;105(37):14082-7 (2008).
- Fernandez-Hernando, C., Ackah, E., Yu., J., Suarez, Y., Murata, T., Iwakiri, Y., Prendergast, J., Miao, R.Q., Birnbaum, M.J. and Sessa, W.C. Loss of Akt1 leads to severe atherosclerosis and occlusive coronary artery disease. Cell Metabolism (6):446-57 (2007).
- Fernandez-Hernando, C., et al. (2006). Identification of Golgi-localized acyl transferases that palmitoylate and regulate endothelial nitric oxide synthase. J. Cell Biol. 174(3):369-77.
- Miao, R.Q., et al. (2006). Identification of a receptor necessary for Nogo-B stimulated chemotaxis and morphogenesis of endothelial cells. Proc. Natl. Acad. Sci. (USA) 103(29):10997-1002.
- Acevedo L, Yu J, Erdjument-Bromage H, Miao RQ, Kim JE, Fulton D, Tempst P,. Strittmatter SM and Sessa WC. (2004). "A new role for Nogo as a regulator of vascular remodeling." Nat Med 10(4): 382-8.