Abstract
Pericytes are mural cells that are found ubiquitously throughout the microvasculature. Their main physiological roles are to support endothelial cells, regulate microvascular blood flow, and respond to perturbations in their microenvironment. Pericytes are sensitive to the metabolic abnormalities that are characteristic of type 2 diabetes mellitus, including dyslipidemia, hyperglycemia, and hyperinsulinemia. As a consequence of these abnormalities, advanced glycation end products, reactive oxygen species, polyol pathway activation, and protein kinase C isoform activation cause pericyte dysfunction and contribute to the pathogenesis of many common complications of type 2 diabetes. Pericyte dysfunction is known to be a contributing factor to the pathogenesis of retinopathy, nephropathy, neuropathy, beta cell dysfunction, and peripheral artery disease in people with type 2 diabetes. Therapies should target pericytes to treat these common diabetic complications.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Almaca, J., Weitz, J., Rodriguez-Diaz, R., Pereira, E., & Caicedo, A. (2018). The pericyte of the pancreatic islet regulates capillary diameter and local blood flow. Cell Metabolism, 27, 630–644 e4.
Armulik, A., Genove, G., & Betsholtz, C. (2011). Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises. Developmental Cell, 21, 193–215.
Birbrair, A., Zhang, T., Wang, Z. M., Messi, M. L., Olson, J. D., Mintz, A., & Delbono, O. (2014). Type-2 pericytes participate in normal and tumoral angiogenesis. American Journal of Physiology. Cell Physiology, 307, C25–C38.
Brownlee, M. (2005). The pathobiology of diabetic complications: A unifying mechanism. Diabetes, 54, 1615–1625.
Cacicedo, J. M., Benjachareowong, S., Chou, E., Ruderman, N. B., & Ido, Y. (2005). Palmitate-induced apoptosis in cultured bovine retinal pericytes: Roles of NAD(P)H oxidase, oxidant stress, and ceramide. Diabetes, 54, 1838–1845.
Caporali, A., Meloni, M., Vollenkle, C., Bonci, D., Sala-Newby, G. B., Addis, R., Spinetti, G., Losa, S., Masson, R., Baker, A. H., Agami, R., Le Sage, C., Condorelli, G., Madeddu, P., Martelli, F., & Emanueli, C. (2011). Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation, 123, 282–291.
Cho, N. H., Shaw, J. E., Karuranga, S., Huang, Y., Da Rocha Fernandes, J. D., Ohlrogge, A. W., & Malanda, B. (2018). IDF diabetes atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Research and Clinical Practice, 138, 271–281.
Cogan, D. G., Toussaint, D., & Kuwabara, T. (1961). Retinal vascular patterns. IV. Diabetic retinopathy. Archives of Ophthalmology, 66, 366–378.
Crawford, C., Kennedy-Lydon, T., Sprott, C., Desai, T., Sawbridge, L., Munday, J., Unwin, R. J., Wildman, S. S., & Peppiatt-Wildman, C. M. (2012). An intact kidney slice model to investigate vasa recta properties and function in situ. Nephron. Physiology, 120, p17–p31.
Dar, A., Domev, H., Ben-Yosef, O., Tzukerman, M., Zeevi-Levin, N., Novak, A., Germanguz, I., Amit, M., & Itskovitz-Eldor, J. (2012). Multipotent vasculogenic pericytes from human pluripotent stem cells promote recovery of murine ischemic limb. Circulation, 125, 87–99.
Defronzo, R. A., Ferrannini, E., Groop, L., Henry, R. R., Herman, W. H., Holst, J. J., Hu, F. B., Kahn, C. R., Raz, I., Shulman, G. I., Simonson, D. C., Testa, M. A., & Weiss, R. (2015). Type 2 diabetes mellitus. Nature Reviews. Disease Primers, 1, 15019.
Ding, L., Cheng, R., Hu, Y., Takahashi, Y., Jenkins, A. J., Keech, A. C., Humphries, K. M., Gu, X., Elliott, M. H., Xia, X., & Ma, J. X. (2014). Peroxisome proliferator-activated receptor alpha protects capillary pericytes in the retina. The American Journal of Pathology, 184, 2709–2720.
Efimenko, A. Y., Kochegura, T. N., Akopyan, Z. A., & Parfyonova, Y. V. (2015). Autologous stem cell therapy: How aging and chronic diseases affect stem and progenitor cells. Bioresearch Open Access, 4, 26–38.
Engerman, R. L. (1989). Pathogenesis of diabetic retinopathy. Diabetes, 38, 1203–1206.
Fernandez Fernandez, B., Elewa, U., Sanchez-Nino, M. D., Rojas-Rivera, J. E., Martin-Cleary, C., Egido, J., & Ortiz, A. (2012). 2012 update on diabetic kidney disease: The expanding spectrum, novel pathogenic insights and recent clinical trials. Minerva Medica, 103, 219–234.
Folli, F., Corradi, D., Fanti, P., Davalli, A., Paez, A., Giaccari, A., Perego, C., & Muscogiuri, G. (2011). The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro- and macrovascular complications: Avenues for a mechanistic-based therapeutic approach. Current Diabetes Reviews, 7, 313–324.
Fong, D. S., Aiello, L., Gardner, T. W., King, G. L., Blankenship, G., Cavallerano, J. D., Ferris, F. L., 3rd, Klein, R., & American Diabetes, A. (2003). Diabetic retinopathy. Diabetes Care, 26, 226–229.
Giacco, F., & Brownlee, M. (2010). Oxidative stress and diabetic complications. Circulation Research, 107, 1058–1070.
Giannini, C., & Dyck, P. J. (1995). Basement membrane reduplication and pericyte degeneration precede development of diabetic polyneuropathy and are associated with its severity. Annals of Neurology, 37, 498–504.
Gubernator, M., Slater, S. C., Spencer, H. L., Spiteri, I., Sottoriva, A., Riu, F., Rowlinson, J., Avolio, E., Katare, R., Mangialardi, G., Oikawa, A., Reni, C., Campagnolo, P., Spinetti, G., Touloumis, A., Tavare, S., Prandi, F., Pesce, M., Hofner, M., Klemens, V., Emanueli, C., Angelini, G., & Madeddu, P. (2015). Epigenetic profile of human adventitial progenitor cells correlates with therapeutic outcomes in a mouse model of limb ischemia. Arteriosclerosis, Thrombosis, and Vascular Biology, 35, 675–688.
Hammes, H. P., Lin, J., Renner, O., Shani, M., Lundqvist, A., Betsholtz, C., Brownlee, M., & Deutsch, U. (2002). Pericytes and the pathogenesis of diabetic retinopathy. Diabetes, 51, 3107–3112.
Haneda, M., Araki, S., Togawa, M., Sugimoto, T., Isono, M., & Kikkawa, R. (1997). Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions. Diabetes, 46, 847–853.
Hayden, M. R., Yang, Y., Habibi, J., Bagree, S. V., & Sowers, J. R. (2010). Pericytopathy: Oxidative stress and impaired cellular longevity in the pancreas and skeletal muscle in metabolic syndrome and type 2 diabetes. Oxidative Medicine and Cellular Longevity, 3, 290–303.
Hayes, K. L., Messina, L. M., Schwartz, L. M., Yan, J., Burnside, A. S., & Witkowski, S. (2018). Type 2 diabetes impairs the ability of skeletal muscle pericytes to augment postischemic neovascularization in db/db mice. American Journal of Physiology Cell Physiology, 314, C534–C544.
Houtz, J., Borden, P., Ceasrine, A., Minichiello, L., & Kuruvilla, R. (2016). Neurotrophin signaling is required for glucose-induced insulin secretion. Developmental Cell, 39, 329–345.
Hu, Y., Chen, Y., Ding, L., He, X., Takahashi, Y., Gao, Y., Shen, W., Cheng, R., Chen, Q., Qi, X., Boulton, M. E., & Ma, J. X. (2013). Pathogenic role of diabetes-induced PPAR-alpha down-regulation in microvascular dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 110, 15401–15406.
Inoguchi, T., Sonta, T., Tsubouchi, H., Etoh, T., Kakimoto, M., Sonoda, N., Sato, N., Sekiguchi, N., Kobayashi, K., Sumimoto, H., Utsumi, H., & Nawata, H. (2003). Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: Role of vascular NAD(P)H oxidase. Journal of American Society of Nephrology, 14, S227–S232.
Isono, M., Chen, S., Hong, S. W., Iglesias-De La Cruz, M. C., & Ziyadeh, F. N. (2002). Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-beta-induced fibronectin in mesangial cells. Biochemical and Biophysical Research Communications, 296, 1356–1365.
Kennedy-Lydon, T. M., Crawford, C., Wildman, S. S., & Peppiatt-Wildman, C. M. (2013). Renal pericytes: Regulators of medullary blood flow. Acta Physiologica (Oxford, England), 207, 212–225.
Kim, J. H., Kim, J. H., Yu, Y. S., Kim, D. H., & Kim, K. W. (2009). Recruitment of pericytes and astrocytes is closely related to the formation of tight junction in developing retinal vessels. Journal of Neuroscience Research, 87, 653–659.
Koya, D., Haneda, M., Nakagawa, H., Isshiki, K., Sato, H., Maeda, S., Sugimoto, T., Yasuda, H., Kashiwagi, A., Ways, D. K., King, G. L., & Kikkawa, R. (2000). Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. The FASEB Journal, 14, 439–447.
Kramann, R., & Humphreys, B. D. (2014). Kidney pericytes: Roles in regeneration and fibrosis. Seminars in Nephrology, 34, 374–383.
Lenoir, O., Jasiek, M., Henique, C., Guyonnet, L., Hartleben, B., Bork, T., Chipont, A., Flosseau, K., Bensaada, I., Schmitt, A., Masse, J. M., Souyri, M., Huber, T. B., & Tharaux, P. L. (2015). Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy, 11, 1130–1145.
Metea, M. R., & Newman, E. A. (2007). Signalling within the neurovascular unit in the mammalian retina. Experimental Physiology, 92, 635–640.
Miyoshi, T., Kennedy, W. R., & Yoon, K. S. (1979). Morphometric comparison of capillaries in muscle spindles, nerve, and muscle. Archives of Neurology, 36, 547–552.
Mizutani, M., Kern, T. S., & Lorenzi, M. (1996). Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. The Journal of Clinical Investigation, 97, 2883–2890.
Pallone, T. L. (1994). Vasoconstriction of outer medullary vasa recta by angiotensin II is modulated by prostaglandin E2. The American Journal of Physiology, 266, F850–F857.
Pallone, T. L., & Silldorff, E. P. (2001). Pericyte regulation of renal medullary blood flow. Experimental Nephrology, 9, 165–170.
Park, F., Mattson, D. L., Roberts, L. A., & Cowley, A. W., Jr. (1997). Evidence for the presence of smooth muscle alpha-actin within pericytes of the renal medulla. The American Journal of Physiology, 273, R1742–R1748.
Park, S. W., Yun, J. H., Kim, J. H., Kim, K. W., Cho, C. H., & Kim, J. H. (2014). Angiopoietin 2 induces pericyte apoptosis via alpha3beta1 integrin signaling in diabetic retinopathy. Diabetes, 63, 3057–3068.
Remuzzi, G., Schieppati, A., & Ruggenenti, P. (2002). Clinical practice. Nephropathy in patients with type 2 diabetes. The New England Journal of Medicine, 346, 1145–1151.
Ritz, E., & Orth, S. R. (1999). Nephropathy in patients with type 2 diabetes mellitus. The New England Journal of Medicine, 341, 1127–1133.
Sakhneny, L., Rachi, E., Epshtein, A., Guez, H. C., Wald-Altman, S., Lisnyansky, M., Khalifa-Malka, L., Hazan, A., Baer, D., Priel, A., Weil, M., & Landsman, L. (2018). Pancreatic pericytes support beta-cell function in a Tcf7l2-dependent manner. Diabetes, 67, 437–447.
Sasson, A., Rachi, E., Sakhneny, L., Baer, D., Lisnyansky, M., Epshtein, A., & Landsman, L. (2016). Islet pericytes are required for beta-cell maturity. Diabetes, 65, 3008–3014.
Shimizu, F., Sano, Y., Abe, M. A., Maeda, T., Ohtsuki, S., Terasaki, T., & Kanda, T. (2011a). Peripheral nerve pericytes modify the blood-nerve barrier function and tight junctional molecules through the secretion of various soluble factors. Journal of Cellular Physiology, 226, 255–266.
Shimizu, F., Sano, Y., Haruki, H., & Kanda, T. (2011b). Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood-nerve barrier by stimulating the release of TGF-beta and vascular endothelial growth factor (VEGF) by pericytes. Diabetologia, 54, 1517–1526.
Shimizu, F., Sano, Y., Maeda, T., Abe, M. A., Nakayama, H., Takahashi, R., Ueda, M., Ohtsuki, S., Terasaki, T., Obinata, M., & Kanda, T. (2008). Peripheral nerve pericytes originating from the blood-nerve barrier expresses tight junctional molecules and transporters as barrier-forming cells. Journal of Cellular Physiology, 217, 388–399.
Stitt, A. W., Li, Y. M., Gardiner, T. A., Bucala, R., Archer, D. B., & Vlassara, H. (1997). Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. The American Journal of Pathology, 150, 523–531.
Stratton, I. M., Adler, A. I., Neil, H. A., Matthews, D. R., Manley, S. E., Cull, C. A., Hadden, D., Turner, R. C., & Holman, R. R. (2000). Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ, 321, 405–412.
Tilton, R. G., Faller, A. M., Burkhardt, J. K., Hoffmann, P. L., Kilo, C., & Williamson, J. R. (1985). Pericyte degeneration and acellular capillaries are increased in the feet of human diabetic patients. Diabetologia, 28, 895–900.
Tilton, R. G., Hoffmann, P. L., Kilo, C., & Williamson, J. R. (1981). Pericyte degeneration and basement membrane thickening in skeletal muscle capillaries of human diabetics. Diabetes, 30, 326–334.
Trost, A., Lange, S., Schroedl, F., Bruckner, D., Motloch, K. A., Bogner, B., Kaser-Eichberger, A., Strohmaier, C., Runge, C., Aigner, L., Rivera, F. J., & Reitsamer, H. A. (2016). Brain and retinal pericytes: Origin, function and role. Frontiers in Cellular Neuroscience, 10, 20.
Valdez, C. N., Arboleda-Velasquez, J. F., Amarnani, D. S., Kim, L. A., & D’amore, P. A. (2014). Retinal microangiopathy in a mouse model of inducible mural cell loss. The American Journal of Pathology, 184, 2618–2626.
Vono, R., Fuoco, C., Testa, S., Pirro, S., Maselli, D., Ferland Mccollough, D., Sangalli, E., Pintus, G., Giordo, R., Finzi, G., Sessa, F., Cardani, R., Gotti, A., Losa, S., Cesareni, G., Rizzi, R., Bearzi, C., Cannata, S., Spinetti, G., Gargioli, C., & Madeddu, P. (2016). Activation of the pro-oxidant PKCbetaII-p66Shc signaling pathway contributes to pericyte dysfunction in skeletal muscles of patients with diabetes with critical limb ischemia. Diabetes, 65, 3691–3704.
Wada, R., & Yagihashi, S. (2005). Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Annals of the New York Academy of Sciences, 1043, 598–604.
Yan, J., Tie, G., Wang, S., Messina, K. E., Didato, S., Guo, S., & Messina, L. M. (2012). Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice. Journal of the American Heart Association, 1, e002238.
Yan, J., Tie, G., Xu, T. Y., Cecchini, K., & Messina, L. M. (2013). Mesenchymal stem cells as a treatment for peripheral arterial disease: Current status and potential impact of type II diabetes on their therapeutic efficacy. Stem Cell Reviews, 9, 360–372.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Hayes, K.L. (2019). Pericytes in Type 2 Diabetes. In: Birbrair, A. (eds) Pericyte Biology in Disease. Advances in Experimental Medicine and Biology, vol 1147. Springer, Cham. https://doi.org/10.1007/978-3-030-16908-4_12
Download citation
DOI: https://doi.org/10.1007/978-3-030-16908-4_12
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-16907-7
Online ISBN: 978-3-030-16908-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)