The endothelium plays a vital role in regulating the contraction and relaxation of vascular smooth muscle. Prostacyclin (PGI2), also known as prostaglandin I2, is one of the substances produced by the endothelium that can induce relaxation of vascular smooth muscle by increasing cyclic adenosine monophosphate (cAMP) levels. PGI2 is synthesized in the endothelium from arachidonic acid and is not mediated by the endothelium itself. Various vasodilator agents, such as adenosine, H+, CO2, and K+, can be released from the surrounding tissue and act locally on resistance vessels to promote relaxation.

Injury to the endothelium of blood vessels precedes the development of atherosclerosis. The endothelium possesses several protective properties that have an antiatherogenic effect. For instance, it regulates the adhesion of leukocytes to the vessel wall, suppresses the proliferation of vascular smooth muscle cells, maintains a smooth vessel lining that resists thrombus formation, and regulates vascular smooth muscle tone. These functions primarily involve the action of nitric oxide (NO), which is produced by the endothelium. NO production is regulated by various substances and shear stress acting on the vessel wall.

The figure (Fig. 17.24) illustrates the mechanisms of endothelium-mediated and non-endothelium-mediated vasodilation. Prostacyclin (PGI2) is generated from arachidonic acid (AA) through the action of cyclooxygenase (CycOx) and PGI2 synthase (PGI2Syn) in the endothelium. It induces relaxation of adjacent vascular smooth muscle by increasing cAMP levels. Stimulation of endothelial cells with acetylcholine (ACh) or other agents results in the formation and release of an endothelium-derived relaxing factor, which is identified as nitric oxide (NO). NO stimulates guanylyl cyclase (GCyc) to elevate cGMP levels in vascular smooth muscle, leading to relaxation. The vasodilator nitroprusside (NP) acts directly on vascular smooth muscle. Adenosine, H+, CO2, and K+ can also rise in the parenchymal tissue and induce vasodilation by directly affecting vascular smooth muscle. Other substances involved in this process include adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine triphosphate (ATP), cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), and L-arginine.

PGI2, which is synthesized from arachidonic acid through the action of PGI2 synthase, is released by the endothelium. The exact mechanism triggering PGI2 synthesis remains unknown, although an increase in shear stress caused by accelerated blood flow may lead to its release. The primary function of PGI2 is to prevent platelet adherence to the endothelium and platelet aggregation, thereby inhibiting the formation of intravascular clots. Additionally, PGI2 induces relaxation of vascular smooth muscle.

However, the most significant contributor to endothelium-mediated vascular dilation is nitric oxide (NO), which is a component of endothelium-derived relaxing factor.
The endothelium is an important source of substances that cause contraction or relaxation of vascular smooth muscle. One of these substances is prostacyclin, or prostaglandin I2 (PGI2). PGI2 can relax vascular smooth muscle via an increase in cyclic adenosine monophosphate (cAMP;
Fig. 17.24 ). PGI2 is formed in the endothelium from muscle; its action is not endothelium mediated. Vasodilator agents such as adenosine, H+, CO2, and K+ may be released from parenchymal tissue and act locally on resistance vessels (see
Fig. 17.24
Lumen Endothelium Interstitial space Relaxation Basement membrane ATP ADP AMP Adenosine Parenchymal tissue cAMP RelaxationcGMP NO NP ACh GCyc L-arg. Vascular smooth muscle Cyc OxPGI2Syn PGI2 AA H+, CO2, K+
Injurytotheendotheliumofbloodvesselsprecedesatherosclerosis.Theprotective(antiatherogenic)effectoftheendotheliumresidesinseveralproperties.Forexample,theendotheliumregulatesadhesionofleukocytestothevesselwall,suppressestheproliferationofvascularsmoothmusclecells,maintainsavesselliningthatresiststheformationofthrombi,andregulatesvascularsmoothmuscletone.AllthesefunctionsinvolvetheactionofNO.Asindicatedpreviously,productionofNOisregulatedbymanysubstancesandbyshearstressactingonthevesselwall.
•Fig. 17.24 Endothelium-Mediated and Non–Endothelium-Mediated Vasodilation. Prostacyclin(PGI2)isformedfromarachidonicacid(AA)bytheactionofcyclooxygenase(CycOx)andprostacyclinsynthase(PGI2Syn)intheendotheliumandelicitsrelaxationoftheadjacentvascularsmoothmuscleviaincreasesincAMP.Stimulationoftheendothelialcellswithacetylcholine(ACh)orotheragents(seetext)resultsintheformationandreleaseofanendothelium-derivedrelaxingfactoridentifiedasnitricoxide(NO).NOstimulatesguanylylcyclase(GCyc)toincreasecGMPinthevascularsmoothmuscletoproducerelaxation.Thevasodilatornitroprusside(NP)actsdirectlyonvascularsmoothmuscle.Substancessuchasadenosine,H+ ,CO2,andK+ canariseintheparenchymaltissueandelicitvasodilationbydirectactiononvascularsmoothmuscle.ADP,adenosinediphosphate;AMP,adenosinemonophosphate;ATP,adenosinetriphosphate;cAMP,cyclicadenosinemonophosphate;cGMP,cyclicguanosinemonophosphate;L-arg,L-arginine.
arachidonic acid, and the process is catalyzed by PGI2 synthase. The mechanism that triggers synthesis of PGI2 is not known. However, PGI2 may be released by an increase in shear stress caused by accelerated blood flow. The primary function of PGI2 is to inhibit platelet adherence to the endothelium and platelet aggregation and thus prevent intravascular clot formation. PGI2 also causes relaxation of vascular smooth muscle.
Of far greater importance in endothelium-mediated vascular dilation is the formation and release of nitric oxide (NO), a component of endothelium-derived relaxing factor (see