16 rhesus monkeys were assigned an atherogenic diet (high cholesterol diet: HCD) and 10 monkeys a control diet (standard diet: SD) after baseline measurements were collected; blood pressure, pulse wave velocity (PWV) and lipid profile. At baseline, cholesterol and triglycerides showed no differences between the control and treated groups. However, at the second follow-up, cholesterol levels in the HCD group increased 2-fold compared to controls (p<0.0001), and remained at plateau until the end of experiment. Arterial tissue was collected at the time of sacrifice. Histochemical observation and morphological analysis indicated that age increases intimal thickness and medial thickness along with atherosclerotic lesions in these domestic monkeys fed normal diets. Interestingly, age dramatically increases fat deposition within arterial walls in the monkeys fed an HCD. We also found that an HCD increases adverse histopathologic events and plaque burden and vulnerability, which are closely associated with changes in cholesterol, diastolic blood pressure, and PWV. Upon further study we found that the HCD reprograms the aged arterial wall via the damage of endothelial integrity and an increase of macrophage infiltration, foam cell formation, and fat or calcium deposits, leading to a vulnerable thickened intima for the accelerated occurrence of adverse vascular wall events, including atherosclerosis and its complications such as plaque vulnerability. Proteomic study of carotid arterial proteins indicates that 8 proteins that were less abundant and 12 proteins that are more abundant in old animals. Proteins that are less abundant in old animals are: Protein S100-A6, Isocitrate dehydrogenase NADP, Myelin P0 protein, Myosin-7, Aldo-keto reductase family 1-member B10, Protein S100-A4, Calmodulin and SPATS2-like protein. Proteins that are more abundant in old animals include: Programmed cell death protein 6, Periostin, Apolipoprotein E, Erythrocyte band 7 integral membrane protein, Translation initiation factor IF-2 Complement component C9, Lactadherin (MFG-E8), Apolipoprotein C-I, Vitronectin, Annexin A7, Cysteine and glycine-rich protein 2, Serine protease HTRA1, Serum amyloid P-component, Complement C1q, and tumor necrosis factor-related protein. Furthermore, micro RNA (miR) arrays of carotid arteries in monkeys fed with or without an HCD indicate that there are 91 totally modified miRs, via a continuous age analysis. Fifteen miRs showed significant change with aging, 67 miRs were significantly different in abundance associated with HCD treatment. During PCR validation, we saw that miR-21, miR-34a, miR-155, miR-210, miR-199a, miR-199a-3p, miR-423-5p, let-7i are indeed modulated with age and/or HCD treatment. Notably, an increased microRNA 34 (miR34) imbalance is known to accompany aging. The effect of this imbalance upon the vascular system and interactions with angiotensin II (Ang II) proinflammation cascade has not yet been determined. The arteries harvested from young (8 mo) and old (30 mo) FXBN rats were collected. miR-34a is upregulated in the aortic walls with aging. In vitro studies have demonstrated that age-associated disequilibrium of miR-34a is mediated by an Ang II signaling loop in VSMCs. Increased Ang II signaling resulted from the miR-34a associated downregulation in Ang II Receptor-Associated Protein (AGTRAP) and situin1 (SIRT1), furthermore, an increase in Ang II signaling contributed to the upregulation of miR-34a with aging. Importantly, both Ang II and miR-34a facilitate an inflammatory response in vascular smooth muscle cells (VSMCs), such as marked increases in milk fat globule EGF-8 (MFG-E8), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase type II (MMP-2), interleukin-6/8 (IL-6/8), transcriptional factor ets-1 and a significant decrease in SIRT1. Interestingly, MFG-E8 increases the proliferation of VSMCs via an acceleration of cell cycle while miR-34a increases the senescence and invasion of VSMCs via a deceleration of cell cycle and activation of MMP-2, respectively. The miR34 disequilibrium that occurs in aged rat arterial walls enhances Ang II proinflammatory signaling, thus driving VSMC phenotypic shifts in a feed forward manner, a key cellular and molecular event for the pathogenesis of hypertension and atherosclerosis. Controlling arterial miR disequilibrium and curbing proinflammation is an evidence-based effective approach to halt the epidemic of hypertension and atherosclerosis in the elderly. It is well known that central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An increase in central arterial wall stiffening, measured as an increase in aortic PWV, is a major risk factor for clinical CV disease events. In rhesus monkeys, a 2-year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening, increases PWV and arterial inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall are driven by genomic and proteomic signatures of oxidative stress and inflammation. Very importantly, resveratrol treatment prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV. Collagen accumulation and remodeling in the vascular wall is a cardinal feature of vascular fibrosis that exacerbates the complications traditionally associated with hypertension, aging, diabetes and atherosclerosis. With no specific therapy available to date, identification of mechanisms underlying vascular fibrogenesis is a clinically relevant goal. Recent studies demonstrated that augmented collagen deposition and adverse matrix remodeling strongly correlate with an increased expression of the collagen-specific receptor tyrosine kinase, Discoidin Domain Receptor 2 (DDR2), in the aorta of rhesus monkeys fed a HFS diet for 24 months. Together with data demonstrating DDR2-dependence of collagen gene expression in vascular cells exposed to hyperglycemic conditions in vitro, these observations provide robust evidence that DDR2 is a hitherto unrecognized determinant of vascular fibrosis associated with vascular pathologies, and hence a druggable target. We also show that resveratrol attenuates collagen deposition and remodeling in the vascular wall via the inhibition of DDR2 expression. In addition, in collaboration with Dr. Engler (Department of Bioengineering, University of California, San Diego), we found when studying the cardiac proteomes of both young and old rhesus monkeys and rats, certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression markedly increased median life span in flies. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity in flies, rats, and monkeys.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Pintus, Gianfranco; Giordo, Roberta; Wang, Yushi et al. (2018) Reduced vasorin enhances angiotensin II signaling within the aging arterial wall. Oncotarget 9:27117-27132
Wang, Mingyi; Monticone, Robert E; McGraw, Kimberly R (2018) Proinflammatory Arterial Stiffness Syndrome: A Signature of Large Arterial Aging. J Vasc Res 55:210-223
AlGhatrif, Majd; Wang, Mingyi; Fedorova, Olga V et al. (2017) The Pressure of Aging. Med Clin North Am 101:81-101
Kaushik, Gaurav; Spenlehauer, Alice; Sessions, Ayla O et al. (2015) Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Sci Transl Med 7:292ra99
Mattison, Julie A; Wang, Mingyi; Bernier, Michel et al. (2014) Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab 20:183-90
Csiszar, Anna; Sosnowska, Danuta; Wang, Mingyi et al. (2012) Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J Gerontol A Biol Sci Med Sci 67:811-20
Ungvari, Zoltan; Bailey-Downs, Lora; Gautam, Tripti et al. (2011) Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66:866-75
Le Couteur, David G; Lakatta, Edward G (2010) A vascular theory of aging. J Gerontol A Biol Sci Med Sci 65:1025-7
Fu, Zongming; Wang, Mingyi; Gucek, Marjan et al. (2009) Milk fat globule protein epidermal growth factor-8: a pivotal relay element within the angiotensin II and monocyte chemoattractant protein-1 signaling cascade mediating vascular smooth muscle cells invasion. Circ Res 104:1337-46