Background
The renin-angiotensin-aldosterone system (RAAS) plays an important role in the development and progression of vascular stiffness, hypertension and accelerated atherosclerosis, which are associated with the metabolic syndrome (MetS) and type 2 diabetes mellitus. In addition to the intima, RAAS plays an important role in vascular media and adventitial remodeling.
Methods
Descending thoracic aortas of young male transgenic heterozygous (mRen2) 27 (Ren2) rats were utilized for ultrastructural study. This lean model of hypertension, insulin resistance, and oxidative stress harbors the mouse renin gene and is known to have increased aortic tissue levels of angiotensin II, angiotensin type 1 receptors, and elevated plasma aldosterone levels. Results
Ultrastructural observations substantiate known and novel findings in the tunica media, internal and external elastic lamina, and tunica adventitia, which includes: increased media collagen - proteoglycan matrix expansion, increased secretory and proliferative activity and migration of vascular smooth muscle cells (VSMCs) into a newly developing subendothelial neointima, increased VSMC caveolae, mitochondria degeneration, apoptosis; and lipid retention at the elastin lamellar interface. Openings in the external elastic lamina allow pericyte-to-VSMC contacts. The tunica adventitia exhibits stromal pericyte hyperplasia with actively synthetic phenotype and pericyte-pericyte connections.
Conclusion
While these studies only represent a single snapshot in time, they provide an evaluation of early abnormal ultrastructural vascular remodeling in Ren-2 models of the conduit-elastic thoracic aorta.
Jia G, Aroor AR, Sowers JR: Arterial stiffness. A Nexus between Cardiac and Renal Disease. Cardiorenal Med 2014;4(1):60-71. doi: 10.1159/000360867
Hayden MR, Habibi J, Joginpally T, Karuparthi PR, Sowers JR. Ultrastructure Study of Transgenic Ren2 Rat Aorta – Part 1: Endothelium and Intima. Cardiorenal Med 2012;2(1):66-82. doi:10.1159/000335565
Wei Y, Whaley-Connell AT, Habibi J, Rehmer J, Rehmer N, Patel K, et al. Mineralocorticoid receptor antagonism attenuates vascular apoptosis and injury via rescuing protein kinase B activation. Hypertension 2009;53(2):158-165. DOI:10.1161/HYPERTENSIONAHA.108.121954
Glagov S. Hemodynamic risk factors: mechanical stress, mural architecture, media nutrition, and the vulnerability of arteries to atherosclerosis. In: The Pathology of Atherosclerosis, Edited by Wissler RW, Geer JC, Kaufman N. Baltimore: Williams and Wilkins; 1972:164.
Geer, JC, Haust MD. Smooth muscle cells in atherosclerosis. In: Monographs on Atherosclerosis, Edited by Pollak OJ, Simms HS, Kirk JE. Basal, Karger; 1972: 39.
Johnson MS, DeMarco VG, Heesch CM, Whaley-Connell AT, Schneider RI, Rehmer NT, et al. Sex differences in baroreflex sensitivity, heart rate variability, and end organ damage in the TGR(mRen2)27 rat. Am J Physiol Heart Circ Physiol 2011;301: H1540-H1550. doi: 10.1152/ajpheart.00593.2011
Wolinsky H. Effects of hypertension and its reversal on the thoracic aorta of male and female rats. Morphological and chemical studies. Circ Res 1971;28(6):622-637. doi:10.1161/01.res.28.6.622
Wiener J, Loud AV, Giacomelli F, Anversa P. Morphometric analysis of hypertension-induced hypertrophy of rat thoracic aorta. Am J Pathol 1977; 88(3):619-634. PMCID:PMC2032372
Amann K, Wolf B, Nichols C, Törnig J, Schwarz U, Zeier M, Mall G, Ritz E. Aortic changes in experimental renal failure: hyperplasia or hypertrophy of smooth muscle cells? Hypertension 1997;29(3):770-775. doi:10.1161/01. hyp.29.3.770
Risler N, Castro C, Cruzado M, González S, Miatello R. Proteoglycans production by aortic vascular smooth muscle cells from hypertensive rats. Biocell 2003; 27(2):189-196. doi:10.1161/01.hyp.34.4.893
Schwartz SM, Stemerman MB, Benditt EP: The aortic intima. II. Repair of the aortic lining after mechanical denudation. Am J Pathol 1975;81(1):15-42. PMID: 1180329
Yamin R, Morgan KG. Deciphering actin cytoskeletal function in the contractile vascular smooth muscle cell. Physiol 2012;590(17):4145-4154. doi: 10.1113/jphysiol.2012.232306
Guyton JR, Lindsay KL, Dao DT. Comparison of aortic intima and inner media in young adult versus aging rats. Stereology in a polarized system. Am J Pathol 1983; 111(2):234-246. PMID: 6846504
Ikari Y, McManus BM, Kenyon J, Schwartz SM. Neonatal Intima Formation in the Human Coronary Artery. Arterioscler Thromb Vasc Biol 1999; 19:2036-2040. doi:10.1161/01.atv.19.9.2036
Russell L, Holman RL, McGill HC Jr, Strong JP, Geer JC. The Natural History of Atherosclerosis. Am J Pathol 1958;34(2):209-235. PMCID: PMC1934740
Nakashima Y, Fujii H, Sumiyoshi S, Wight TN, Sueishi K. Early human atherosclerosis. Accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration. Arterioscler Thromb Vasc Biol 2007;27:1159–1165. doi:10.1161/ATVBAHA.106.134080
Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362(6423):801-809. DOI:10.1038/362801a0
Raines EW, Ross R: Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis. Br Heart J 1993;68(1 suppl):S30-S37. doi: 10.1136/hrt.69.1_suppl. s30
Kwon HM, Kang S, Hong BK, Kim D, Park HY, Shin MS, Byun KH. Ultrastructure changes of the external elastic lamina in experimental hypercholesterolemic porcine coronary arteries. Yonsei Med J 1999;40(3):273-282. doi:10.3349/ymj.1999.40.3.273
Wolinsky H. Long-term effects of hypertension on the rat aortic wall and their relation to concurrent aging changes. Morphological and chemical studies. Circ Res 1972;30(3):301-309. doi:10.1161/01.res.30.3.301
Arribas SM, Briones AM, Bellingham C, Gonzalez MC, Salaices M, Liu K, et al. Heightened aberrant deposition of hard-wearing elastin in conduit arteries of prehypertensive SHR is associated with increased stiffness and inward remodeling. Am J Physiol Heart Circ Physiol 2008;295(6):H2299-H2307. doi: doi.org/10.1152/ajp-heart.00155.2008
McGrath JC, Deighan C, Briones AM, Shafaroudi MM, McBride M, Adler J, et al. New aspects of vascular remodeling: the involvement of all vascular cell types. Exp Physiol 2005;90(4):469-475. doi:10.1113/exp-physiol.2005.030130
Lassègue B & Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol. 2003;285: R277–R297. doi:10.1152/ajpregu.00758.2002
Fortuño A, San José G, Moreno MU, Díez J & Zalba G. Oxidative stress and vascular remodeling. Exp Physiol 2005;90:457–462. doi:10.1113/expphysiol.2005.030098
Touyz RM. Intracellular mechanisms involved in vascular remodeling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol. 2005;90:449–455. doi:10.1113/expphysiol. 2005.030080
Britton KA, Fox CS. Perivascular adipose tissue and vascular disease. Clin Lipidol. 2011;6(1):79-91. doi: 10.2217/clp.10.89
Arribas SM, Hillier C, González C, McGrory S, Dominiczak AF, McGrath JC. Cellular aspects of vascular remod-eling in hypertension revealed by confocal microscopy. Hypertension 1997;30(6):1455-1464. doi:10.1161/01. hyp.30.6.1455
Hayden MR, Karuparthi PR, Habibi J, Wasekar C, Lastra G, Manrique C, Stas S, Sowers JR. Ultrastructural islet study of early fibrosis in the Ren2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell. JOP 2007; 8(6):725-738. PMID:17993725
Hayden MR, Karuparthi PR, Habibi J, Lastra GL, Patel K, Wasekar C, et al. Ultrastructure of islet microcirculation, pericytes and the islet exocrine interface in the HIP rat model of diabetes. Exp Biol Med (Maywood). 2008;233(9):1109-1123. doi: 10.3181/0709-RM-251
Hayden MR, Patel K, Habibi J, Gupta D, Tekwani SS, Whaley-Connell A, Sowers JR. Attenuation of endocrine-exocrine pancreatic communication in type 2 diabetes: pancreatic extracellular matrix ultrastructural abnormalities. J Cardiometab Syndr 2008;3(4):234-243. doi:10.1111/j.1559-4572.2008.00024.x
da Silva Meirelles L, Chagastelles PC, Nardi NB: Mesenchymal stem cells reside in virtually all postnatal organs and tissues. J Cell Sci 2006;119(Pt 11):2204-2213. doi: 10.1242/jcs.02932
Dore-Duffy P, Katychev A, Wang X, Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab 2006;26(5):613-624. doi:10.1038/sj.jcbfm.9600272
Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res 2005;97(6):512-523. doi:10.1161/01.RES.0000182903.16652.d7
Allt G, Lawrenson JG. Pericytes: cell biology and pathology. Cells Tissues Organs. 2001;169(1):1-11. doi:10.1159/000047855
Sims DE. The pericyte. A review. Tissue Cell 1986;18:153-174. doi:10.1016/0040-8166(86)90026-1
Hayden MR, Sowers JR. Isletopathy in Type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress. Antioxid Redox Signal 2007;9(7):891-910. doi: 10.1089/ars.2007.1610
Andreeva ER, Pugach IM, Gordon D, Orekhov AN. Continuous subendothelial network formed by pericyte-like cells in human vascular bed. Tissue Cell 1998; 30(1):127-135. https://doi.org/10.1016/S0040-8166(98)80014-1
Mitchell GF, Hwang SJ, Vasan RS et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 2010; 121(4): 505–511. doi:10.1161/CIRCULATIONAHA.109.886655.
DeMarco VG, Habibi J, Jia G et al. Low-Dose mineralocorticoid receptor blockade prevents Western diet-induced arterial stiffening in female mice. Hypertension 2015;66(1):99-107. doi: 10.1161/HYPERTENSIO-NAHA.115.05674
Weisbrod RM, Shiang T, Al Sayah L, Fry JL, Bajpai S, Reinhart-King CA, et al. Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hyperten-sion 2013;62(6):1105-1110. doi:10.1161/HYPERTEN-SIONAHA.113.01744.
Wolinsky H, Glagov S. Comparison of abdominal and thoracic aortic medial structure in mammals. Circ Res 1969;25(6):677-686. doi:10.1161/01.res.25.6.677
Dingemans KP, Teeling P, Lagendijk JH, Becker AE. Extracellular matrix of human aortic media: An ultrastructural histochemical and immunohistochemical study of human aortic media. Anat Rec 2000;258(1):1-14. doi:10.1002/(SICI)1097-0185(20000101)258:1<1::AID-AR1>3.0.CO;2-7
Wolinsky H, Glagov S. A Lamellar Unit of Aortic Medial Structure and Function in Mammals. Circ Res 1967;20(1):99-111. DOI:10.1161/01.RES.20.1.99
Chaldakov GN, Vankov VN. Morphological aspects of secretion in the arterial smooth muscle cell, with special reference to the Golgi complex and microtubular cytoskeleton. Atherosclerosis 1986; 61: 175-192.
Chaldakov GN. GEORGE E. PALADE LECTURE. Human body as a multicrine system, with special reference to cell protein secretion: From vascular smooth muscles to adipose tissue. Biomed Rev 2016; 27: VIII-XIX
Majesky MW, Dong XR, Hoglund V, Mahoney WM Jr, Daum G. The adventitia: a dynamic interface containing resident progenitor cells. Arterioscler Thromb Vasc Biol 2011;31(7):1530-9. doi: 10.1161/ATVBAHA.110.221549.
Majesky MW, Dong XR, Hoglund V, Daum G, Mahoney WM Jr. The adventitia: a progenitor cell niche for the vessel wall. Cells Tissues Organs 2012;195(1-2):73-81. doi: 10.1159/000331413.
Email this article (Login required) 
