Endothelial Function

Luecha BoontaveekulDepartment of Physiology

Functions of Endothelial CellBarrier and transportationTarget cell for humoral and cellular immune responseConverting enzyme providerVascular tone regulationCoagulation and fibrinolysisProduction of VSMC proliferation

Objective

เพื่อใหรูถึงหนาที่ทั่วไปของ Endothelial cell เพื่อใหทราบการเปลี่ยนแปลงหนาที่ของ Endothelial cell ถาเซลลอยูในพยาธิสภาพบางชนิด เพื่อเปนพื้นฐานสําหรับศึกษาตอทาง เภสัชวิทยา พยาธิวิทยา และทางคลินิก

Functions of Endothelial CellBarrier and transportationTarget cell for humoral and cellular immune responseConverting enzyme providerVascular tone regulationCoagulation and fibrinolysisProduction of VSMC proliferation

TransportationRemind to Starling forces

3 types of capillaryContinuous: muscle, lung, brainFenestrated: intestine, kidney, endocrine glandDiscontinuous: (sinusoid): bone, liver, spleen

Intercellular transportationThrough large and small pore

WaterWater-insoluble lipid

Histamine

ReceptorG protein

PLCPIP2

IP3DAG

SR

Ca2+MLCK?PKC?

Roundup

Functions of Endothelial CellBarrier and transportationTarget cell for humoral and cellular immune responseConverting enzyme providerVascular tone regulationCoagulation and fibrinolysisProduction of VSMC proliferation

Adhesion and Migration of WBC

Major Family of Adhesion MoleculesSelectin (glycoprotein)

P-selectin (platelet and endothelial cell)L-selectin (WBC)E-selectin (endothelial cell)

β2-integrin of circulating cellsCD11/CD18

Immunoglobulin superfamilyICAM-1 (intercellular adhesion molecule)VCAM-1 (vascular cell adhesion molecule)PECAM-1 (platelet-endothelial cell adhesion molecule)

Adhesion and Migration of WBC

PAF=platelet activating factorMCP=monocyte chemotactic protein

TNF-α, -γ, IL-1 and IL-4

Functions of Endothelial CellBarrier and transportationTarget cell for humoral and cellular immune responseConverting enzyme providerVascular tone regulationCoagulation and fibrinolysisProduction of VSMC proliferation

Endothelium

Vascular smooth muscle

Autoregulation

WBC

Platelets(serotonin,

TXA2)

Local vasodilatingsubstance

histamine, substance P

Endothelium-derived factors

Local Control

Endothelium-derived factorsDilating factors

Endothelium-derived relaxing factor (EDRF, NO)Prostacyclin (PGI2)Endothelium-derived hyperpolarizing factor (EDHF)

Constricting factorEndothelinAngiotensin IIThromboxane A2

Dilating factorsVS

Constricting factors

NO, at first discovery, named as EDRF (endothelium relaxing factor)PGI2

EDHF (endothelium derived hyperpolarizing factor)

Not NO and PGI2

Hyperpolarization of endothelial cell and VSMCOpen K channel

AgonistNO

ACh, Catecholamine, Bradykinin, Histamine, Substance PThrombin, Serotonin, ADP (จาก platelet aggregation)Shear stress

PGI2, EDHFBradykinin, Substance P, Acetylcholine

Endothelin21-aa peptide hormone3 types: Endothelin-1, -2, and –3Structure similar to sarafotoxin (Israel snake venom)ET-1 effect on CVS: vasoconstriction and vascular smooth muscle proliferationRole of ET-2 and –3 ?

Cytokines and hormonesTGF-β, AT II, Insulin

Hypoxia

Preproendothelins

Big endothelins, proendothelins

Endothelin

Endopeptidase

Endothelin converting enzyme(ECE)

NO, ANP, prostaglandin E2and prostacyclin, shear stress

2 Types of endothelin receptors in blood vessels

ETA receptorVascular smooth muscleVasoconstrictionBlocker: BQ-123

ETB receptorEndothelial cellsVasodilation via NO, PGI2

Blocker (both receptors): Bosentan

Physiologic role of EndothelinDiphasic response of intravenous endothelin administration

Vasodilation before vasoconstrictionSmall dose of ET

vasodilation

Role of endothelin in diseasesHypertension: บทบาทยังไมชัดเจนLDL กระตุนใหสราง ET เพิ่มขึ้น ซึ่ง ET ทําใหมี VSMC proliferation ใน AtherosclerosisMyocardial ischemia กระตุนการสราง ETCHF พบวามรีะดับ ET เพิ่มขึน้

Angiotensin IITissue RAS

Angiotensinogen, ACE, AII receptor in vascular endothelium (renin?)

Two type of Angiotensin II receptorAT1 receptor (AT1R)

Vasoconstriction, aldosterone release etcVSMC proliferation, hypertrophy and antiapoptotic effect

AT2 receptor (AT2R)apoptotic effect

Factors increase VSMC proliferationGrowth factors e.g. FGFAngiotensin IICatecholamine via α1 adrenergic receptorEndothelin via ETA receptorThrombinIL-1, IL-6

Factors increase VSMC proliferationHypoxia (but hyperoxia inhibits proliferation)InjuryMechanical forces: stretch, pressure or shear stressOxygen radical species e.g. O2

-, H2O2and OH-

Endothelial injuryภยันตรายที่เกดิกับ endothelial cell

Denudation injury: เซลลตายและลอกหลุด

Non-denudation injury: เซลลยังไมตาย แตหนาที่เสียไป

Denudation injury

Denuded endothelium Blood-subendothelial direct contact

Inflammation, WBC & Platelet adhesion

Blood clot formation

Endothelial regeneration

VSMC proliferation

Vascular remodeling

Endothelial dysfunction

Regenerated endotheliumDecreased release of relaxing factors esp. responding to serotonin, α2-adrenergic agonist, platelet aggregation, thrombinserotonin-caused exaggerated vasoconstrictionabnormal hemostatic homeostasis

Non-denudation injuryCell swellingintercellular junction/space wideninglipid deposition in endothelial cellWBC and Plt adhesionmatrix infiltration into intercellular and subendothelial space => denudation

Non-denudation injury (functional changes)

Increase in permeability Decreased release of EDRFIncreased release of EDCFimbalance of vasomotor regulationVSMC changesabnormal hemostatic homeostasis

Causes of endothelial injuryDirect traumaReperfusion injuryLipids (cholesterol, LDL, oxidized LDL)Infection and inflammationDMSmokingSharply increase of BP