Review articles

By Ms. Ramica Sharma , Dr. Ac Rana , Mr. Chetan Kumar , Dr. Seema Thakur
Corresponding Author Ms. Ramica Sharma
Rayat Institute of Pharmacy, Railmjra - India 144514
Submitting Author Ms. Ramica Sharma
Other Authors Dr. Ac Rana
Rayat Institute of Pharmacy, Pharmacology Dept, Railmajra, Dist SBS Ngar - India 144514

Mr. Chetan Kumar
Rayat Institute of Pharmacy, Pharmacology Dept, Railmajra, Dist, SBS Nagar - India 144514

Dr. Seema Thakur
PCTE Institute of Pharmacy, Pharmacy Dept, Ludhiana - India 141001


Vascular endothelial dysfunction (VED) endothelial nitric oxide synthase (eNOS) Inflammatory Mediators, Rheumatoid Arthritis, Cardiovascular disordes, Asthma, Alzheimer

Sharma R, Rana A, Kumar C, Thakur S. Endothelium Dysfunction, Inflammation and Cardiovascular Disorder. WebmedCentral PHARMACEUTICAL SCIENCES 2011;2(9):WMC002176
doi: 10.9754/journal.wmc.2011.002176
Submitted on: 08 Sep 2011 01:02:42 PM GMT
Published on: 09 Sep 2011 05:36:13 PM GMT


Vascular endothelium maintains tone and free flow of blood in vessels Several studies indicate that the impairment in the maintenance of vascular tone results in vascular endothelial dysfunction (VED) results from reduced activation of endothelial nitric oxide synthase (eNOS) Various inflammatory mediators are also upregulated during VED Inflammation is a trait of several diseases including rheumatoid arthritis, Alzheimer's disease, asthma and various cardiovascular disorders Interestingly few recent studies demonstrated the role of various inflammatory mediators in the progression of VED and vascular disease associated with this Hence the present review has been designed to delineate the role of various inflammatory mediators in the pathogenesis of inflammation-induced VED


Vascular endothelium maintains tone and free flow of blood in vessels Several studies indicate that the impairment in the maintenance of vascular tone results in vascular endothelial dysfunction (VED) results from reduced activation of endothelial nitric oxide synthase (eNOS) Various inflammatory mediators are also upregulated during VED Inflammation is a trait of several diseases including rheumatoid arthritis, Alzheimer's disease, asthma and various cardiovascular disorders Interestingly few recent studies demonstrated the role of various inflammatory mediators in the progression of VED and vascular disease associated with this Hence the present review has been designed to delineate the role of various inflammatory mediators in the pathogenesis of inflammation-induced VED

Inflammation and Cardiovascular Disorders

Inflammation and Cardiovascular Disorders
Recent studies indicate that inflammatory mediators are implicated in the pathogenesis of various cardiovascular and inflammatory disorders that occur due to VED and their role has burgeoned It has been reported that in United States Atherosclerosis a major inflammatory cardiovascular disorder is one of the leading causes of mortality and disability [30-31]. Atherosclerosis is a multifactorial multistep disease that involves chronic inflammation and plaque rupture [32]. In atherosclerosis the normal functions of the endothelium are distorted that results in aggagerating an inflammatory response [33]. These lipoprotein particles can undergo oxidative modification like that of LDL and activate inflammatory functions of vascular endothelial cells [34]. Further cytokines peroxides and other substances released in response to injury may hassle endothelial cells to express P-selectin ICAM-1 and E-selectin which in turn persuade process of leucocyte adhesion and subsequently their migration leading to formation of fatty streak formation [35]. Further Urotensin II (U-II) basically a cyclic undecapeptide is found in high concentration in atheromatous lesions [36,37] . U-II accelerates foam cell formation and proliferation of VSMC suggesting development of atherosclerotic plaque [38-40]. Beside this inflammation was also implicated in pathogenesis of hypertension [41-42]. and various cardiovascular disorder by increasing the expression of C-RP [43-44] and activating Rennin Angiotensin Aldosterone System (RAAS) and elevates the blood pressure [45-46]. Plasma CRP concentrations also predicts the risk of myocardial infarction (MI) and ischemic stroke [47]. Angiotensin II is the main culprit responsible for triggering vascular inflammation by inducing oxidative stress resulting in up-regulation of pro-inflammatory transcription factors such as NF-kB [27,48-50]. These in turn regulate the production of various inflammatory mediators that lead to endothelial dysfunction and vascular injury [41,46-47]. Elevated plasma levels of proinflammatory cytokines and chemokines such as interleukin (IL)-1 IL-6 fractalkine and monocyte chemoattractant protein-1 (MCP-1) currently known as CC chemokine ligand 2 (CCL2) has been elicted in the pathogenesis of pulmonary hypertension [26]. Further various studies elict the importance of IL-6 in both acute and chronic inflammation as it act as the main inducer of acute phase reactants such as C-reactive protein fibrinogen and serum amyloid A protein [51] .In addition to this there is inhibition of caveolin that causes proliferation of VSMC [52]. Neopterin is secreted by macrophages following stimulation by the cytokine interferon-g and is a susceptible marker for the activation of the cell-mediated immune system [53-54] .The serum level of neopetrin is found to be elevated in patients with unstable angina and acute MI compared [55] Fig 2 shows the pathogenesis of inflammation-induced cardiovascular disorders.


Inflammation induce-VED has been revealed to be involved in pathogenesis of various vascular disorders by inducing C-RP urotensin and increasing the expression of various inflammatory mediators. Rho-kinase was also found to be upregulated and actively involved in Inflammation and vascular pathogenesis.


We wish to express our gratitude to Prof AC Rana (Director) Sh Nirmal Singh Rayat and S Gurwinder Bahara (Chairman) Rayat institute of Pharmacy Railmajra for his praise worthy suggestion and constant support for this study.


1. Feletou M, Vanhoutte PM. Endothelial dysfunction a multifaceted disorder. Am J Physiol, 2006,291,H985-1002.
2. Balakumar P, Sharma R and Singh M. Benfotiamine attenuate nicotine and uric acid-induced vascular endothelial dysfunction in rats. Pharmacological Res, 2008,58,356363.
3. Satttar N. Inflammation and endothelial dysfunction. intimate companions in the pathogenesis of vascular disease Clin Sci, 2004,106,. 443445.
4. Shimokawa H, Matoba T. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pharmacol Res, 2004,49,543549.
5. Ignarro LJ, Byrn RE, Buga GM , Wood KS, Chaudhuri G. Pharmacological evidence that endothelium-derived relaxing factor is nitric oxide. use of pyrogallol and superoxide dismutase to study endothelium-dependent and nitric oxide-elicited vascular smooth muscle relaxation. J Pharmacol Exp Therap. 1988, 181-189.
6. Ignarro LJ. Nitric oxide in the regulation of vascular function. an historical overview. J Cardiol, 2002,17,301-306.
7. Balakumar P, Chakkarwar VA, Krishan P, Singh and M. Vascular endothelial dysfunction. A tug of war in diabetic nephropathy. Biomed Pharmacotherapy, 2009,63, 171-179.
8. Davignon J, Ganz P.Role of endothelial dysfunction in atherosclerosis. Circulation 2004,109,27-32.
9. Nakagami H, Kaneda Y, Ogihara T, Morishita R.Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. Curr Diabetes Rev, 2005,1, 59-63.
10. Quyyumi A, Patel S. Endothelial Dysfunction and Hypertension. Cause or Effect Hypertension,2010, 55,1092-1094.
11. Khan F, Cohen RA, Rudermann NB, Chipkin SR, Coffman JD. Vasodilator response in forearm skin of patient with Insulin-dependent diabetes mellitus. Vasc Med, 1996,1,187-193.
12. U Hink, LiH Mollnau, M Oelze, E Matheis, M Hartmann. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res, 2001,88,14-22.
13. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T.Endothelial dysfunction oxidative stress and risk of cardiovascular events in patients with coronary artery disease. Circulation, 2001,104,2673-2703.
14. Roquer J, Segura T, Serena J, Castillo J.Endothelial dysfunction, vascular disease and stroke. the ARTICO study. Cerebrovasc Dis, 2009,27,25-37.
15. Endemann DH and Schiffrin EL. Endothelial dysfunction. J Am Society Nephrology, 2004,15,1983-1992.
16. Pennathur S and Heinecke JW. Oxidative stress and endothelial dysfunction in vascular disease. Curr Diabetes Rep, 2007,10,257-264.
17. Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE. Chronic inflammation. importance of NOD2 and NALP3 in interleukin-1b generation. Clin Exp Imm, 2006,147,227235.
18. Verma S, Reddy K, Balakumar P.The Defensive Effect of Benfotiamine in Sodium Arsenite-Induced Experimental Vascular Endothelial Dysfunction. Biol Trace Elem Res, 2010, 101007/s12011-009-8567-7.
19. Balakumar P, Singh M. Different role of rho-kinase in pathological and physiological cardiac hypertrophy in rats. Pharmacol, 2006,78,91-97.
20. Koyanagi M, Kitamoto S, Usui M, Kaibuchi K, Kataoka HC, Egashira K et al. Important Role of Rho-kinase in the Pathogenesis of Cardiovascular Inflammation and Remodeling Induced by Long-Term Blockade of Nitric Oxide Synthesis in Rats. Hypertension, 2002,39,245-250.
21. Segain JP, Raingeard D, Bletiere de la, Sauzeau V, Bourreille A, Hilaret G et al . Rho-kinase blockade prevents inflammation via nuclear factor kappa B inhibition. evidence in Crohn's disease and experimental colitis. Gastroenterology, 124; 2003.1180-1187.
22. Brown JH, Del Re DP, Susssman MA.The Rac and Rho hall of fame. a decade of hypertrophy signalling hits. Circ Res, 2006,98,730-742.
23. Nohria A, Grunert ME, Rikitake Y, Noma K, Prsic A, Ganz P et al. Rho kinase inhibition improves endothelial functions in human subjects with coronary artery disease. Circ Res, 2006,99,14261432.
24. Feinberg MW, Shimizu K, Lebedeva M, Haspel R, Takayama K, Chen Z et al.Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation. Circ Res, 2004,19,601-608.
25. Shireman PK, Contreras-Shannon V, Ochoa O, Karia BP, Michalel JE, McManus LM. MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration. J Leukoc Biol, 2007, 81,doi. 101189/jlb0506356.
26. Zhang W, Rojas M, Lilly B, Tsai NT, Lemtalsi T, Liou GI et al. NAD(P)H oxidase dependent regulation of CCL2 production during retinal inflammation. Invest Ophthalmol Vis Sci, 209, 50, 3033-3040.
27. Dhindsa S, Garg R, Bandyopathyay A, Dandona PN. Angiotensin II and Inflammation. The Effect of ACE Inhibition and Angiotensin II Receptor Blockade. Metabolic Syndrome and Related Disorders, 2003,4, 255-259.
28. Ferder L, Inserra F, Mart nez-Maldonado M. Inflammation and the metabolic syndrome. role of angiotensin II and oxidative stress. Curr Hypertens Rep, 2006, 8, 191-198.
29. Ridker PM, Hennekens CH, Buring JE. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med, 2000,342,836843.
30. Shear CL, Pouleur HG, Ryder SW, Orloff DG. Biomarkers in the Prevention and Treatment of Atherosclerosis. Need Validation and Future. Pharmacol. Reviews, 2007,59,40-53.
31. Hansson GK. Inflammation Atherosclerosis and Coronary Artery Disease. NEJM, 2005,352,1685-1695.
32. Libby P, Ridker PM, Maseri A. Inflammation and Atherosclerosis. Circulation, 2002,105,1135-1143.
33. Paoletti R, Gotto AM, Hajjar Jr DP. Inflammation in Atherosclerosis and Implications for Therapy. Circulation, 2004,109,III-20 III-26.
34. Kaperonisa EA, Liapisa CD, Kakisisb JD, Dimitroulisa D, Papavassiliouc VG. Inflammation and Atherosclerosis. Eur. J. Vasc. Endo. Vasc. Surg, 2006,31,386-393.
35. Schauer IE, Knaub LA, Lloyd M, Watson PA, Gliwa C, Lewis KE et al. CREB. Downregulation in Vascular Disease. A Common Response to Cardiovascular Risk. Arterioscl Thromb Vasc Bio,2010, 30,733-741.
36. Watanabe T, Suguro T, Kanome T, Sakamoto Y, Kodate S, Hagiwara T et al .Human Urotensin-II Accelerates Foam Cell Formation in Human Monocyte-Derived Macrophages. Hypertension, 2005,46,738-744.
37. Mallamaci F, Cutrupi, S, Pizzini P, Tripepi G, Zoccali C. Urotensin II and Biomarkers of Endothelial Activation and Atherosclerosis in End-Stage Renal Disease. Am J Hyp, 2006,19,505510.
38. Suguro T, Watanabe T, Ban Y, Kodate S, Misaki A, Hirano T, Miyazaki A, Adachi M. Increased Human Urotensin II Levels Are Correlated With Carotid Atherosclerosis in Essential Hypertension. Am J Hyp, 2007,20,211217.
39. Cheung BM, Leung R, Man YB, Wong LY. Plasma concentration of urotensin II is raised in hypertension, J Hypertens, 2004, 22, 13411344.
40. Ng LL, Loke I, OBrien RJ, I B Squire, Davies JE. Plasma urotensin in human systolic heart failure. Circulation, 2002,106,28772880.
41. Androulakis E, Tousoulis D, Papageorgiou N, Tsioufis C, Kallikarzaros L, Stefanadis C. Essential Hypertension. Is There a Role for Inflammatory Mechanisms Cardiol Rev, 2009,17, 216-221.
42. Mathew R. Inflammation and Pulmonary Hypertension. Cardiol in Rev, 2010, 18, 67-72S.
43. Brianna R, Sandra PR, Joseph BM, Benjamin DH, Chloe AA, Chloe M, Tami LB, John FC, Abdallah GK, Jeffery LA. C - reactive protein Predicts Death in Patients with Non-Ischemic Cardiomyopathy. Cardiology, 2005,104,196-201.
44. Bucova M, Bernadic M, Buckingham M. C-reactive protein cytokines and inflammation in cardiovascular disease. Bratisl Lek Listy, 2008,109,333-340.
45. Rompe F, Unger T, Steckelings UM. The angiotensin AT2 receptor in inflammation Drug News Perspect, 2010, 23, 104-111.
46. Savoia C, Schiffrin EL. Vascular inflammation in hypertension and diabetes. molecular mechanisms and therapeutic interventions Clinical Science, 2007, 112, 375384.
47. Savoia C, Schiffrin EL . Inflammation in hypertension. Curr Opin Nephrol Hypertens, 2006, 15, 152-158.
48. Clapp BR, Hirschfield GM, Storry C, Gallimore JR, Stidwilll RP, Singer M et al. Inflammation and Endothelial Function Direct Vascular Effects of Human C - reactive protein on Nitric Oxide Bioavailability. Circulation, 2005, 111, 1530-1536.
49. Ruiz-Ortega M, Esteban V, Ruperez M, Sanchez-Lopez E, Rodriguez-Vita J, Carvajal G et al. Renal and vascular hypertension-induced inflammation. Role of angiotensin II. Pathophysiology of hypertension. Current Opinion in Nephrology & Hypertension, 2006, 15, 159-166.
50. Vaziri ND, Bai Y, Ni Z, Quiroz Y, Pandian R, Rodriguez-Iturbe B. Intra-Renal Angiotensin II/AT1 Receptor Oxidative Stress Inflammation and Progressive Injury in Renal Mass Reduction. JPET, 2007, 323, 8593.
51. Silvio D, Bin G. Interleukin-6. a therapeutic Jekyll and Hyde in gastrointestinal and hepatic diseases. Gut, 2010, 59, 149-151.
52. Cohen AW, Hnasko R, Schubert W, Lisanti MP. Role of Caveolae and Caveolins in Health and Disease. Physiol Rev, 2004, 84, 1341-1379.
53. Hatzistilianou KH, Eboriadou M, Papastavrou T, Magnesali C, Pappa S. Neopterin and circulating adhesion molecules as prognostic markers in childhood asthma. Arch Med Sci, 2007, 3, 123-128.
54. Fuchs D, Weiss G, Wachter H. Neopterin biochemistry and clinical use as a marker for cellular immune reactions Int Arch Allergy Immunol,1993, 101, 1-6.
55. Garcia-Mol X, Cole D, Zouridakis E, Kaski JC. Increased serum neopterin. a marker of coronary artery disease activity in women. Heart, 2000, 83, 346-350.

Source(s) of Funding


Competing Interests



This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party.
Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

0 comments posted so far

Please use this functionality to flag objectionable, inappropriate, inaccurate, and offensive content to WebmedCentral Team and the authors.


Author Comments
0 comments posted so far


What is article Popularity?

Article popularity is calculated by considering the scores: age of the article
Popularity = (P - 1) / (T + 2)^1.5
P : points is the sum of individual scores, which includes article Views, Downloads, Reviews, Comments and their weightage

Scores   Weightage
Views Points X 1
Download Points X 2
Comment Points X 5
Review Points X 10
Points= sum(Views Points + Download Points + Comment Points + Review Points)
T : time since submission in hours.
P is subtracted by 1 to negate submitter's vote.
Age factor is (time since submission in hours plus two) to the power of 1.5.factor.

How Article Quality Works?

For each article Authors/Readers, Reviewers and WMC Editors can review/rate the articles. These ratings are used to determine Feedback Scores.

In most cases, article receive ratings in the range of 0 to 10. We calculate average of all the ratings and consider it as article quality.

Quality=Average(Authors/Readers Ratings + Reviewers Ratings + WMC Editor Ratings)