Recent Advances in the Pathophysiological Role Of Nitric

Oxide In Endothelial Tissue

Auriell Frederick
4/21/2014

RECENT ADVANCES IN THE ROLE OF NO

Abstract
Nitric oxide functions as pertinent protective agent in endothelial tissue of the cardiac system. NO
is mostly released from its enzymatic precursor, nitric oxide synthase. Its roles are widespread, acting to
control vascular tone and central blood perfusion, inhibit platelet aggregation thus preventing the
formation of thrombi, maintain metabolism of the L-arginine pathway, and provides a central defense to
pathological conditions including atherosclerosis, diabetes, arterial wall hypertension, and coronary
arterial disease which occurs from endothelial damage in vivo.

RECENT ADVANCES IN THE ROLE OF NO

Recent Advances in the Pathophysiological Role of Nitric Oxide In Endothelial Tissue
Recent and interesting advances in the pathophysiological role of nitric oxide (NO) in human
endothelial tissue in the cardiac system have been discovered which have allowed a better understanding
of clinical disease and implications of the presence or absence of NO. The L-arginine NO pathway has
been proven to play a ubiquitous role in internal endothelial vasculature especially in cellular respiration.
NO modulates smooth muscle cell proliferation and maintains vasodilator tone, inhibits platelet
aggregation, and provides collateral circulation of blood, maintaining systemic perfusion (Porth, C.M.,
and Matfin, G., 2005, p.469). NOs pathway works in tandem with endothelium-derived growth factor
(the biochemistry of nitric oxide) which is synthesized from the amino acid L-arginine. This pathway is
centrally vital to the maintenance of vascular physiology, including: mediation of cellular defense and
neurotransmitter function in both the peripheral and central nervous (Moncada & Higgs, 2006).
Endothelial cells lining the blood vessels, including the coronaries, barricade blood from arterial
walls. The structure of the elastic vasculature allow for vasoconstriction and dilation. The contraction and
relaxation of arterial smooth muscle walls is dependent on several substances internally released from
endothelial tissue. Such molecules are potent vasodilators including: prostacyclin, endothelium derived
hyperpolarizing factor (EDHF), and most importantly, NO. Products occurring from thrombin, increased
shear force, and aggregating platelets stimulate the generation and release of NO. Vasoconstrictors are
also released via endothelial tissue and include vasoconstriction factors, primarily endothelins (Porth,
C.M., and Matfin, G., 2005, p.537).
All blood vessel types are dilated by vascular NO via the stimulation of soluble guanylyl cyclase
and increased cyclical guanosine monophosphate in (cGMP) smooth muscle cells. (The discovery of
nitric oxide and its role in vascular biology) Besides the great inhibition of platelet aggregation and
adhesion, NO can also prevent leukocyte adhesion to the vessel walls. These implications are important,
as leukocyte adherence occurs as an early event of atherosclerosis; a disease characterized fibrous plaques

RECENT ADVANCES IN THE ROLE OF NO

within the vessels and arteries resulting from adhesion with scar tissue formation. NO interferes with the
interleukin molecules CD11 and CD18 by inhibiting its ability to form an adhesive bond with on
endothelial surface. This normative inhibitory function may provide protection against early onset
atherogenesis (Frstermann & Mnze, 2005) and other pathophysiological diseases such as vasospasm
and hypertension (Moncada & Higgs, 2006). Furthermore, NO also plays a role in a later step of
atherogenesis by inhibiting mitogenesis, DNA synthesis, and proliferation of smooth muscle cells. This
functions to provide protection to against smooth muscle from exposure to platelet-derived growth
factor(s) via the inhibition of platelet aggregation and adhesion. Considering the combination of these
preventative effects, NO likely serves as the most important antiatherogenic defense principle in
endothelial tissue. (Moncada & Higgs, 2006).
The NO pathway also regulates cellular respiration via mitochondrial systems which enhance the
production of reactive oxygen species (ROS). Increased ROS production is indicated in increased
cardiovascular risk factors. Electron flow within nitric oxide synthase is regulated very strictly. If
disturbed, the ferrous-dioxygen complex dissociates, the resulting product is O2 instead of NO
(Frstermann &Mnzel, 2005).
Approximately 10^14 endothelial cells serve to protect the body from vascular disease
atherosclerosis and thrombosis by the aid of endothelial nitric oxide synthase (eNOS), a molecule which
generates the vasoprotective enzyme nitric oxide (NO). Oxidative stress occurs from the excess
production of superoxide (O2), which reacts with NO, forming peroxynitrite a powerful oxidant. The
enzymatic activity of eNOS generate peroxynitrite (ONOO-) and which eventually only produces O2.
(Frstermann & Mnzel, 2005) and initiates cellular apoptosis.
Clinical conditions of his oxidative species have been implicated and established in
pathophysiological conditions including hypercholesterolemia, diabetes mellitus, and coronary artery
disease. Substantive evidence exists (with regard to the increased ROS formation in vessel endothelium).

RECENT ADVANCES IN THE ROLE OF NO

Antioxidants treat these clinical pathologies by enhancing endothelium-dependent vasodilation through
coronary and forearm circulation in individuals afflicted from CAD and diabetes (Tousoulis, Kampoli,
Tentolouris, , Papageorgiou, & Stefanadis, 2012).
Aforementioned is the tightly control electron flow within NOS and if disturbed NOS uncoupling
may occur. The ferrous-dioxygen complex dissociates, and O2 is generated from the oxygenase domain
instead of NO. Recent research advances attribute the NOS-catalyzed reduction of oxygen to O2 by the
failure of the enzyme to dimerize. NOS isomers, monomers, and the occasional isolated reductase
domains act sufficiently for superoxide generation, however, dimeric NOS isoforms have increased
enzymatic activity. Current studies also suggest that the evidence of dimer formation implies that the
isoform is unchangeable once dimerization occurs, that is, the isoform shall not return to its monomer.
This uncoupling of oxygen reduction via NO formation also is unlikely to provide any significant
enzymatic monomerization in vivo (Frstermann &Mnzel, 2005).
Alternatively, a few recent studies indicate that endothelial cardiovascular risk factors stem from
decreased eNOS expression. The suggested mechanism by which this occurs is thought to be through the
excess production of hydrogen peroxide H2O2, which is the dismutation product of O2. The excess
production of H202 gives rise to a superoxide effect, which has the ability to interfere with
dioxyribonuclease (DNA) activity and expressivity by increasing the eNOS expression, thus effecting its
transcriptional and posttranscriptional mechanisms (Frstermann.& Mnzel, 2005).
Risk factors that decrease the function of the protective endothelial vasculature include: cigarette
smoking, high serum glucose, high levels of serum low density lipoprotein (LDL), and hypertension.
Decreased endothelial generation of NO has been implicated in numerous cardiovascular diseases,
including pulmonary arterial hypertension and atherosclerosis, which share nearly identical traditional
cardiovascular disease risk factors. Decreased endothelial generation of NO reduces endothelial
protection which results in the failure of blood platelet aggregation and adhesion inhibition leading to

RECENT ADVANCES IN THE ROLE OF NO

thrombus formation, hypertension, and vasoconstriction, all presenting with a central schema of specific
pathophysiological criteria; endothelial dysfunction. NO is detected via a decrease in endotheliumdependent vasodilation.
Now widely accepted, a definition of endothelial dysfunction is simply described as decrease in
endothelial NO. In early stages, this characteristic dysfunction has additionally been observed prior to any
evidence of cardiovascular disease (in patients with history of familial essential hypertension). A major
risk factor and predictor of the presence of cardio vascular disease associated with endothelial dysfunction
is cigarette smoking. Cigarette smoking is though mainly to reduce the bioavailability of NO. This results
from its chemical ROS, namely O2. Another suggested mechanism of endothelial dysfunction is the
modification of eNOS substrates within its cofactors; including L-arginine or tetrahydrobiopterin
(BH4).Alternatively, cigarette smoking may decrease the production of NO by reducing expression of
eNOS in endothelial tissue (Moncada & Higgs, 2006).
In conclusion, vascular biology has been majorly impacted by the role of NO and its regulatory
functions. Its interactions provide a foundation of research knowledge which can soon be translated
clinically based on its risk factors for endothelial dysfunction when nitric oxide bioavailability is lost.
Impaired endothelial function results from the promotion of vessel wall inflammation and may cause the
formation of extracellular matrix deposit, the occurrence of cellular apoptosis, blood platelet aggregation,
thrombi formation, serum lipidemia, lipid-deposit, and possibly smooth muscle proliferation. All of these
impairments of endothelial function to contribute to congestive heart disease, essential hypertension,
atherosclerosis, diabetes, and an increasing list of pathophysiological cardiac disease which may result in
atherosclerosis. Therapeutic treatment may stem from the enhancement of endogenous nitric oxide
production or exogenous supplemental nitrous oxide donation. Much research and further investigation
(for treatment reliability) is needed for this novel approach to restore endothelial function.

RECENT ADVANCES IN THE ROLE OF NO

References
Frstermann, U., and Mnzel, T., (2005). Endothelial nitric oxide synthase in vascular disease: from
marvel to menace. American Heart Association, 113:1708-1714
Porth, C.M., and Matfin, G.,( 2005). Pathophysiology: concepts of altered health states p.469, 537
S. Moncada & E.A. Higgs (2006). The discovery of nitric oxide and its role in vascular biology. British
Journal of Pharmacology 147, S193S201
Tousoulis, D., Kampoli, A.M., Tentolouris, C., Papageorgiou, N., and Stefanadis, C., ( 2012). The role of
nitric oxide on endothelial function. Current Vascular Pharmacology, 10, 4-18