Endothelial Dysfunction and Arterial Stiffness: Elucidating the mechanisms of the underlying pathophysiological changes

Pulse wave velocity (PWV) is a well-established measure of large elastic arterial stiffness and has been found to be a powerful predictor of cardiovascular disease in the aging population. It is well known that increased vascular stiffness, as  measured using PWV, signifies declining vascular function and is associated with elevated cardiovascular risk. For example, changes in the arterial wall including increased collagen deposition and degradation of elastin, have been associated with changes in mechanical properties of the artery which may be investigated using ex vivo aortic ring preparations. The following are examples of how researchers have integrated in vivo PWV with isolated vessel preparations to examine the potential mechanisms of pathogenesis.

Soucy et al. investigated the roll of endothelial nitric oxide synthase (eNOS) and its state of phosphorylation as contributing factors to age-related arterial stiffening in rats. Using isolated aortic ring sections, the team demonstrated an endothelium-dependent vasorelaxation response which was significantly diminished in aged vessels¹. This tissue-level endothelial dysfunction was then investigated on a system-level, where the PWV was found to be significantly higher in older rats¹.

To further elucidate the underlying mechanisms of arterial stiffening, a study by LaRocca et al. investigated the role of mitochondrial stress and dysfunction in age-related pathology. This group found that trehalose, a nutraceutical, normalized the mitochondrial quality control markers associated with dysfunction and had a protective effect as shown by improvements to PWV measurements and mechanical stiffness².

In a more recent study, Soucy et al. examined the role of xanthine oxidase (XO) activation in radiation induced cardiovascular disease. The group investigated whether dietary inhibition of XO would protect against vascular injury. As expected from previous studies related to reactive oxygen species (ROS), the exposure of the animals to gamma radiation impaired endothelium-dependent vasorelaxation in aortic ring sections³. Amplified XO activity is known to elevate ROS production, so as expected, when XO activity was inhibited, there was a protective effect observed. PWV, as a measure of arterial stiffness, was found to be significantly elevated in irradiated animals when compared to control and treated groups³. Furthermore, the inhibition of XO was found to protect from radiation-induced endothelial dysfunction and associated cardiovascular complications³.

The above studies are just three of many examples of researchers working towards gaining a better understanding of the underlying mechanisms associated with arterial stiffness and endothelial dysfunction. A combined approach that includes both tissue- and system-level studies is required to fully understand the complex pathological changes that occur with cardiovascular disease.

Scintica Instrumentation offers the tools necessary to perform Pulse Wave Velocity measurements, as well as a wire myography systems to study the mechanical properties of vessels. Click to learn more

These three examples of studies completed to elucidate the underlying mechanisms causing pathological changes associated with arterial stiffness and endothelial dysfunction are just a few from a large body of work. A combined approach, using tissue- and system-level investigations is required to fully understand the complex changes associated with not only age related cardiovascular changes, but also those changes associated with diabetes, atherosclerosis, and even radiation exposure.

Scintica Instrumentation offers the tools necessary to perform Pulse Wave Velocity measurements, as well as a wire myography systems to study the mechanical properties of vessels. Click to learn more about our Doppler Flow Velocity System and our Small Vessel Myography solution. Questions? Feel free to send us a message (sales@scintica.com) or call our applications specialists (+1 519 914 5495).

References:

1. Soucy KG, Ryoo S, Benjo A, Lim HK, Gupta G, Sohi JS, Elser J, Aon MA, Nyhan D, Shoukas AA, Berkowitz DE. Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness. J Appl Physiol. 2006 Dec;101(6): 1751-9.
2. LaRocca TJ, Hearon CM Jr, Henson GD, Seals DR. Mitochondrial quality control and age-associated arterial stiffening. Exp Gerontol. 2014 Oct;58:78-82.
3. Soucy KG, Lim HK, Attarzadeh DO, Santhanam L, Kim JH, Bhunia AK, Sevinc B, Ryoo S, Vazquez ME, Nyhan D, Shoukas AA, Berkowitz DE. Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta. J Appl Physiol. 2010 May;108(5):1250-8.

Additional references using both Pulse Wave Velocity and Small Vessel Myography to study endothelial dysfunction and arterial stiffness:

Fitch RM, Rutledge JC, Wang YX, Powers AF, Tseng JL, Clary T, Rubanyi GM. Synergistic effect of angiotensin II and nitric oxide synthase inhibitor in increasing aortic stiffness in mice. Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1190-8.

Lim HK, Lim HK, Ryoo S, Benjo A, Shuleri K, Miriel V, Baraban E, Camara A, Soucy K, Nyhan D, Shoukas A, Berkowitz DE. Mitochondrial arginase II constrains endothelial NOS-3 activity. Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3317-24.

Kim JH, Bugaj LJ, Oh YJ, Bivalacqua TJ, Ryoo S, Soucy KG, Santhanam L, Webb A, Camara A, Sikka G, Nyhan D, Shoukas AA, Ilies M, Christianson DW, Champion HC, Berkowitz DE. Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats. J Appl PHysiol 2009 Oc;107(4):1249-57.

Yang R, Sikka G, Larson J, Watts VL, Niu X, Ellis CL, Miller KL, Camara A, Reinke C, Savransky V, Polotsky VY, O’Donnell CP, Berkowitz DE, Barouch LA. Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia. Am J Physiol Heart Circ Physiol. 2011 Apr;300(4):H1467-76.

Zhou RH, Vendrov AE, Tchivilev I, Niu XL, Molnar KC, Rojas M, Carter JD, Tong H, Stouffer GA, Madamanchi NR, Runge MS. Mitochondrial oxidative stress in aortic stiffening with age: the role of smooth muscle cell function. Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):745-55.

Jung SM, Jandu S, Steppan J, Belkin A, An SS, Pak A, Choi EY, Nyhan D, Butlin M, Viegas K, Avolio A, Berkowitz DE, Santhanam L. Increased tissue transglutaminase activity contributes to central vascular stiffness in eNOS knockout mice. Am J Physiol Heart Circ Physiol. 2013 Sep 15;305(6):H803-10.

LaRocca TJ, Gioscia-Ryan RA, Hearon CM Jr, Seals DR. The autophagy enhancer spermidine reverses arterial aging. Mech Ageing Dev. 2013 Jul-Aug;134(7-8):314-20.

Du B, Ouyang A, Eng JS, Fleenor BS. Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice. Am J Physiol Heart Circ Physiol. 2015 Jun 1;308(11):H1382-90.

Walker AE, Henson GD, Reihl KD, Morgan RG, Dobson PS, Nielson EI, Ling J, Mecham RP, Li DY, Lesniewski LA, Donato AJ. Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness. J Physiol. 2015 Apr 15;593(8):1931-43.

Agbor LN, Ibeawuchi SC, Hu C, Wu J, Davis DR, Keen HL, Quelle FW, Sigmund CD. Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism. JCI Insight. 2016 Nov 7;1(19):e91015.

Lesniewski LA, Seals DR, Walker AE, Henson GD, Blimline MW, Trott DW, Bosshardt GC, LaRocca TJ, Lawson BR, Zigler MC, Donato AJ. Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell. 2017 Feb;16(1):17026.

Hori D, Dunkerly-Eyring B, Nomura Y, Biswas D, Steppan J, Henao-Meja J, Adachi H, Santhanam L, Berkowitz DE, Steenbergen C, Flavell RA, Das S. miR-181b regulates vascular stiffness age dependently in part by regulating TGF-beta singaling. PLoS One. 2017 Mar 21;12(3):e0174108.