**1. Introduction**

[73] Gitto E, Romeo C, Reiter RJ, Impellizzeri P, Pesce S, Basile M, Antonuccio P, Tri‐ marchi G, Gentile C, Barberi I, Zuccarello B. Melatonin reduces oxidative stress in

[74] Iriti M, Faoro F. Bioactivity of grape chemicals for human health. Nat Prod Commun

[75] Walters-Laporte E, Furman C, Fouquet S, Martin-Nizard F, Lestavel S, Gozzo A, Le‐ sieur D, Fruchart JC, Duriez P, Teissier E. A high concentration of melatonin inhibits in vitro LDL peroxidation but not oxidized LDL toxicity toward cultured endothelial

[76] Joy T, Hegele RA. Is raising HDL a futile strategy for atheroprotection? Nat Rev

[77] Jaimungal S, Wehmeier K, Mooradian AD, Haas MJ. The emerging evidence for vita‐ min D-mediated regulation of apolipoprotein A-I synthesis. Nutr Res 2011;31(11)

[78] Ragbir S, Farmer JA. Dysfunctional high-density lipoprotein and atherosclerosis.

[79] Andrews KL, Moore XL, Chin-Dusting JP. Anti-atherogenic effects of high-density lipoprotein on nitric oxide synthesis in the endothelium. Clin Exp Pharmacol Physiol

[80] Van Lenten BJ, Hama SY, de Beer FC, Stafforini DM, McIntyre TM, Prescott SM, La Du BN, Fogelman AM, Navab M. Anti-inflammatory HDL becomes pro-inflammato‐ ry during the acute phase response. Loss of protective effect of HDL against LDL oxi‐

dation in aortic wall cell cocultures. J Clin Invest 1995;96(6) 2758-2767.

surgical neonates. J Pediatr Surg 2004;39(2) 184-189; discussion 184-9.

cells. J Cardiovasc Pharmacol 1998;32(4) 582-592.

Drug Discov 2008 ;7(2) 143-155.

Curr Atheroscler Rep 2010;12(5) 343-348.

2009;4(5) 611-634.

26 Current Trends in Atherogenesis

805-812.

2010;37(7) 736-742.

Currently the onset and progression of atherosclerosis have been established as the result of different cellular and molecular alterations that are not inevitable but rather predictable and so modifiable, if recognized on time [1,2].

From a morphologic point of view the vascular wall (common to each artery, vein or capilla‐ ry of blood and lymphatic circulation) is made by three layers or *tunicae*: *the tunica intima*starting from the inner and containing the endothelium, directly facing blood; *the tunica media*-with longitudinally oriented layers of smooth muscle cells connected by elastic and collagen fibers, that change the thickness according to the vascular type and function; and *the tunica adventitia*- the most external layer, containing *vasa vasorum,* necessary to maintain high metabolic requirements in larger vessels and the source of endothelial progenitors in neovasculogenesis [3-5].

However in this complex and specialized architecture, the endothelium layer certainly rep‐ resents the first sensor of hemodynamic stress [6] and the favorite target for atherogenic fac‐ tors, like circulating inflammatory molecules, macrophages, lipoproteins (LDLs) and many drugs [7].

Therefore in this scenario it is necessary to update the knowledge on the endothelium, which is the main player in the initial step of atherogenesis, and its involvement in a pivotal biological mechanism, called endoplasmic reticulum (ER) stress, associated to cardiovascu‐ lar damage and invalidating pathologies such as stroke, cardiac ischemia, chronic renal fail‐ ure, macular degeneration and obesity [8-11].

In particular we elucidate here the importance of the ER stress in the artery wall, because it very recently has emerged as a novel event able to promote athero-susceptibility and hyper‐

© 2013 Stacchiotti et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

tension both in animal models and in clinical patients [11,12]. Remarkably this event is early detectable in the endothelial cells [13], sometimes concurrent with other well-known athero‐ genic processes, like inflammation, oxidative damage and endothelial cell death.

phenotypes that change their common flat shape and assume a polygonal morphology to‐ gether with a different turnover. These events are linked to the susceptibility of a specific vessel to develop atherosclerosis and to the onset of valve calcification in the heart [30-32].

Endoplasmic Reticulum Stress in the Endothelium: A Contribution to Athero-Susceptibility

http://dx.doi.org/10.5772/53024

29

So endothelial dysfunctions may have serious consequences and a direct impact on the en‐ dothelial cells' role and activities, mainly on the resistance to dangerous stimuli that pro‐

Indeed they involve different structural and functional aspects of the endothelium, that is classified as a monocellular squamous type of epithelium [34], lining human vascular and lymphatic tree, poorly detectable by traditional light microscopy but well characterized by

Nevertheless the real consideration of the endothelium by physicians has begun about 50 years ago, but only in the last decade, it has obtained more importance in the cardiovascular community, with the rediscovery of Weibel-Palade bodies and caveole signals, the role of transcytosis mechanism, and the active participation into vascular permeability [38-40].

Among most critical structural changes linked to endothelial dysfunctions, there are the reduc‐ tion of glycocalix, which is the external component necessary to react against toxic apoB LDL, and the over-development of fundamental organelles like Golgi complex and the ER [41,42].

Remarkably the ER signaling in the vascular wall is the main topic of this chapter, because much more attention must be given to ER homeostasis in atheroprone sites in the artery tree, resulting from a chronic adaptive reaction to flow disturbance, concurrent with oxidative

Abnormal ER activity has been recently reported in coronary arteries during altered he‐ modynamic changes, diagnosed by genetic techniques as an abnormal transcription of se‐ lected genes; while, in contrast, the transcriptional activity is lacking in more resistant

Remarkably it must be pointed out that, in mammalian epithelial cells, the ER is commonly depicted by ultrastructural analysis as a perinuclear network of tubules and membranes, and by tomography as a dynamic assembly of tridimensional stacks associated to mitochon‐

Moreover it is well-known that the ER has different specialization and structure, called rough or smooth, if associated or not to ribosomes in the same cell, but in specialized cardiac and smooth muscle cells in the vascular wall it is called the sarcoplasmic reticulum [50,51].

Anyway, this dynamic organelle represents the elective site where nascent polypeptide chains are gradually converted in a stable tertiary structure, that is associated to a specific

Among the main ER functions have been comprised the folding of neo-synthesized secreto‐ ry and trans-membrane proteins, the regulation of calcium balance and the synthesis of lip‐

mote the onset of pro-atherogenic vascular damage recently reviewed by [33].

electron microscopy and related techniques [35-37].

damage and inflammation [43,44].

ids, like steroids and cholesterol [53].

arterial beds [45,46].

dria [47-49].

protein [52].

Nevertheless considering the focal distribution of plaques and their cumulative progression during the whole lifespan [14], it is mandatory to consider the role of ER stress signaling in the circulatory bed, in order to maintain the proper ER function, so preventing or reducing the progression into irreversible cardiovascular dysfunctions, such as atherosclerosis, hyper‐ tension and ischemic heart disease [15-17].

We firmly believe that focusing integrated basic and applied research on ER stress in the ar‐ tery tree and in the heart might open new avenues in the treatment and management of in‐ validating cardiovascular complications [18,19].
