M.Y.A.Mawla 1

ENDOTHELIAL DYSFUNCTION(ED) in

ERECTILE DYSFUNCTION(ED)

ED=ED

M.Y.ABDEL_MAWLA,MD

Zagazig Faculty of Medicine,EGYPT

M.Y.A.Mawla 2

Causes of Erectile Dysfunction(ED)

Endothelial dysfunctionED

Smoking Hypogonadism

Endocrine Disorders

Hypertension

Hyperlipidemia

Alcohol abuse

Drug abuseAnemia

Trauma/surgery topelvis or spine

Peyronie’s disease

Vascular surgery

Depression

M.Y.A.Mawla 3

M.Y.A.Mawla 4

The Endothelium

M.Y.A.Mawla 5

LUMEN

Tunica adventitia

Tunica media

Tunica intima

M.Y.A.Mawla 6

M.Y.A.Mawla 7

Note the individual Endothelial Cells

M.Y.A.Mawla 8

M.Y.A.Mawla 9

M.Y.A.Mawla 10

Vasoconstriction and dilatation

Normal Vasoconstriction Vasodilatation

M.Y.A.Mawla 11

VasoconstrictionVasodilatation

Vasoconstriction and dilatation

↓ Resistance to flow ↑ Resistance to flow

M.Y.A.Mawla 12

Endothelial Apoptosis

Normal Apoptosed

M.Y.A.Mawla 13

The EndotheliumAs an Endocrine Organ

M.Y.A.Mawla 17

Vascular Endothelial Mediators• Nitric oxide (NO)

• Cycloxygenase (CxO)

• Endothelin-1 (ET-1)

• Endothelium Depolarisation Factor (EDF)

• Prostanoids

• Angiotensin

• Rho/Rho-kinase

• Prostaglandin E &prostacyclin (cAMP pathway).

M.Y.A.Mawla 18

• Half-life of NO, is affected by its chemical reaction and inactivation by superoxide anion

• NO is the most abundant free-radical in the body

• It is the only biological molecule in high concentrations to out-compete superoxide dismutase for superoxide

• NO has an anti-thrombogenic & anti-atherogenic role

Nitric Oxide (NO)

M.Y.A.Mawla 19

Nitric Oxide(NO)/cGMP PATHWAY

• Relaxation of the smooth muscle trabeculae of the corpus cavernosum (CC)1 and of the helicine arteries leads to blood filling of the sinuses, occlusion of the venous outflow& penile erection.

• Nitric oxide (NO), generated by both nerves & the endothelial cells that cover the trabeculae of the CC, through stimulation of soluble guanylate cyclase and the generation of cyclic GMP play a dominant role in relaxation of smooth muscle in this tissue.

• Other signaling pathways involving vasoactive intestinal polypeptide/cAMP may also be operative in relaxation of the CC.

• Severe erectile dysfunction((ED) in cGMP-dependent kinase 1-deficient mice, with normal cAMP signaling, shows the importance of PKG and the inability of the cAMP pathway to compensate for the absence of the cGMP signaling cascade in vivo .

M.Y.A.Mawla 20(L-NMMA) = N(G)-mono-methyl-L-arginine

M.Y.A.Mawla 21

Endothelial NO has the following actions

• Smooth muscle relaxation and vasodilatation

• Essential for regulation of blood pressure

• Reduces proliferation of vascular smooth muscle

• Protects blood vessel intima from injurious consequences of platelet aggregation

Protective actions of NO

M.Y.A.Mawla 22

NO deficiency in the vessel wall promotes

• Inflammation

• Oxidation of lipoproteins

• Smooth muscle proliferation

• Accumulation of lipid rich material

• Platelet activation and thrombus formation

ED and NO ↓

M.Y.A.Mawla 23

NO induces synthesis of cGMP by stimulation of GC leading to relaxation of myosin (muscle protein)

M.Y.A.Mawla 24

M.Y.A.Mawla 25

• Acetylcholine stimulates the endothelial cells to produce NO, which penetrates into and activates the muscle cells causing relaxation.

M.Y.A.Mawla 26(L-NMMA) = N(G)-mono-methyl-L-arginine

M.Y.A.Mawla 27

(L-NMMA) = N(G)-mono-methyl-L-arginine

(L-NMMA) = N(G)-mono-methyl-L-arginine

M.Y.A.Mawla 28

29M.Y.A.Mawla

Regulatory Functions of the EndotheliumNormal Dysfunction

Vasodilation VasoconstrictionNO, PGI2, EDHF,

BK, C-NPROS, ET-1, TxA2,

A-II, PGH2

Thrombolysis Thrombosis

Platelet Disaggregation

NO, PGI2

Adhesion Molecules

CAMs, P,E Selectins

Antiproliferation

NO, PGI2, TGF-, Hep

Growth Factors

ET-1, A-II, PDGF, ILGF, ILs

Lipolysis Inflammation

ROS, NF-B

PAI-1, TF-α, Tx-A2tPA, Protein C, TF-I, vWF

LPLVogel R

M.Y.A.Mawla 30

Endothelium –derived vasoconstrictors vs Vasodilators

Contractoion- mediating transmitters

• Endothelin• Prostanoids• Angiotensin• Rho A/Rho-kinase

Relaxation-mediating transmitters

• Nitric oxide & cGMP pathway

• Prostaglandin E, prostacyclin& cAMP pathway

M.Y.A.Mawla 31

Endothelium-derived vasodilators Functions

relax vascular smooth muscle in both arteries and veins

NO and PGI2 also inhibit platelet aggregationNO also interferes with the vascular inflammatory

process by decreasing the adhesive interactions between the endothelium and circulating leukocytes, thus interfering with the atherosclerotic process

M.Y.A.Mawla 32

Endothelin peptides

• Endothelin-1(ET-1):synthesied by lacunar endothelium & trabecular muscle

• It induces contraction,via ETA receptors in penile smooth muscles( corpus cavernosa&cavernosal artery).

• Contraction : dependent upon increased intracellular calcium via:

1. Transmembrane calcium flux2. Mobilization of inositol,1,4,5-triphosphate

(IP3)-dependent calcium stores

M.Y.A.Mawla 33

Endothelin-1, a 21-amino-acid peptide, is the predominant isoform of the endothelin peptide family that includes ET-2, ET-3, and ET-4Endothelin-1 is produced primarily by endothelial cells but can also be synthesized by vascular smooth muscle cells (VSMCs) and by macrophagesThe action of ET-1 are mediated by 2 receptor subtypes, ETA and ETB receptors

Endothelin peptides

M.Y.A.Mawla 34

Endothelin• ETA receptor mediate the vasoconstrictor effects of the peptide, ETB

receptors on the endothelium stimulates synthesis of NO• Increased ET-1 associated with decreased endothelium-dependent

vasodilation, a reduction in the biologic actions of NO, and an increased production of oxygen-derived free radicals

• These effects are thought to contribute to heightened vasoconstriction and increased blood pressure increased monocyte adhesion to the vascular wall increased thrombosis a vascular inflammatory response

augmented proliferation of VSMCs

M.Y.A.Mawla 35

Prostanoids

• Several prostanoids:PGI &thromboxane

• Synthesized from arachidonic acid via activity of cycloxygenase in human corpus cavernosa.

• Synthesis :modulated by oxygen tension &hypoxia.

• They are responsible for tone & spontaneous activity of trabecular muscle.

M.Y.A.Mawla 36

Rho A/Rho-kinase• Rho A: a member of Ras low molecular weight of

GTP-binding protein.• Both Rho A &Rho –kinase :in different cellular

functions including smooth muscle contraction.• Human endothelial &corpus cavernosa smooth

muscle cells express these proteins.• RhoA/Rho-kinase signal transduction

pathway:signal mediator of endothelial cell function. Rho-mediated Ca2+sensitization of cavernosal smooth muscle maintains the flaccid (contracted) state.

• This pathway supppresses eNOS gene expression in endothelium.

M.Y.A.Mawla 37

Angiotesin

• Renin-angiotensinsystem maintains penile smooth muscle tone.

• Angiotensin 11 evokes smoth muscle contraction of human corpus cavernosa muscle via relevent receptor & increased IP3 &increased intracellular calcium

M.Y.A.Mawla 38

Nitric Oxide(NO)/cGMP PATHWAY

• Relaxation of the smooth muscle trabeculae of the corpus cavernosum (CC)1 and of the helicine arteries leads to blood filling of the sinuses, occlusion of the venous outflow& penile erection.

• Nitric oxide (NO), generated by both nerves & the endothelial cells that cover the trabeculae of the CC, through stimulation of soluble guanylate cyclase and the generation of cyclic GMP play a dominant role in relaxation of smooth muscle in this tissue.

• Other signaling pathways involving vasoactive intestinal polypeptide/cAMP may also be operative in relaxation of the CC.

• Severe erectile dysfunction in cGMP-dependent kinase 1-deficient mice, with normal cAMP signaling, also demonstrated the importance of PKG and the inability of the cAMP pathway to compensate for the absence of the cGMP signaling cascade in vivo .

M.Y.A.Mawla 39

Endothelial production of vasoactive factors

Normal endothelium is pivotal in the maintenance of normal vascular homeostasis through a balanced production of vasodilator and vasoconstrictor substances

• Endothelium-derived vasodilators

• Endothelium-derived vasoconstrictors

M.Y.A.Mawla 40

Endothelium-derived vasodilators

• Nitric oxide (NO)• Adrenomedullin• Endothelium-derived hyperpolarizing factors• Prostacyclin (PGI2)relax vascular smooth muscle in both arteries and

veins NO and PGI2 also inhibit platelet aggregationNO also interferes with the vascular inflammatory

process by decreasing the adhesive interactions between the endothelium and circulating leukocytes, thus interfering with the atherosclerotic process

M.Y.A.Mawla 41

VasoconstrictorsFrom the sympathetic nerves, circulation,

endothelium

• Norepinephrine (NE)

• Angiotensin II

• Thromoxane A2

• 5-hydroxyeicosatetaraenoic acid (5-HETE)

• Endothelin (ET)-1

M.Y.A.Mawla 42

Endothelium-dependent vasodilator and vasoconstrictor mechanisms

M.Y.A.Mawla 43

Endothelium-derived NO & vascular tone

• NO-a potent mediator of vascular relaxation through action on soluble cGMP in VSMC to inhibit ca-dependent contraction

• NO synthesis & release occurs continuously under basal conditions & can be increased through activation of muscarinic, thrombin, purinergic, and ETB receptors in the endothelial-cell plasma membrane that mediate the actions of acetylcholine, thrombin, ADP, and ET-1 respectively

• Changes in vascular wall shear forces associated with increased flow also increase NO release

• Sustained increase in BP-by continuous administration of stereoselective inhibitors of NO synthase further indicates-NO is important in maintenance a vasodilated state.

M.Y.A.Mawla 44

M.Y.A.Mawla 45

M.Y.A.Mawla 46

M.Y.A.Mawla 47

M.Y.A.Mawla 48

M.Y.A.Mawla 49

ENOTHELIUM DYSFUNCTION(ED)

M.Y.A.Mawla 50

Endothelial Dysfunction

DILATATIONNitric Oxide

1. Prostaglandin E1 &cAMP pathway

Constriction•Endothelin peptides

•Angiotensin•Prostacyclins

•Rho A/RhoA-kinase

Age

Family history

Smoking

Hypertension

Low HDL-C

High LDL-C

Diabetes Mellitus

M.Y.A.Mawla 51

The Mechanism of the Assocation Between Endothelium&Erectile

Dysfunction

vascular etiologyvascular etiology

Endothelial dysfunctionEndothelial dysfunction SmoothSmooth--muscle cell muscle cell abnormalitiesabnormalities

atherosclerotic plaques developing

flow-limited

erectile dysfunction

M.Y.A.Mawla 52

M.Y.A.Mawla 53

The roles of two forms of nitric oxide synthase in cavernosal smooth muscle relaxation and the initiation and maintenance of penile erection

Watts

M.Y.A.Mawla 54

Risk Factors for Development of Endothelium& Erectile

Dysfunction• Diabetes Mellitus (DM)

• Insulin Resistance Syndrome.

• Cigarette Smoking

• Hypertension

• Atherosclerosis &Hyperlipidemia

M.Y.A.Mawla 55

Endothelial dysfunction in DM

M.Y.A.Mawla 56

NO and endothelial dysfunction in diabetes

• Type 1 diabetes--impaired endothelium-dependent vasodilation in response to acetylcholine and similar agonists that stimulate the release of NO

• Type 1 and 2 diabetes—endothelium-dependent vasodilatory responses to brachial artery infusions of acetylcholine, methacholine, and similar agonists are impaired in the forearm

• In normotensive type 2 diabetes—demonstration of blunted endothelium-dependent vasodilation suggests that the endothelial abnormalities cannot be ascribed solely to the impaired endothelium-dependent vasodilation

• Contribution of prostaglandins to abnormalities in endothelial function is minimal

M.Y.A.Mawla 57

M.Y.A.Mawla 58

Mechanisms of impaired endothelium-derived vasodilation in diabetes

• Biologic actions of NO are diminished in diabetes, but production of NO is actually increased

• Increase in the production of ROS by several vascular components in diabetics

• Interactions of NO & superoxide anion within the microenvironment of the vessel wall-- inactivation of NO & formation of the potent oxidant radical, peroxynitrite (OONO-)

M.Y.A.Mawla 59

Mechanisms of impaired endothelium-derived vasodilation in diabetes

• The ratio of NADH/NAD+ :increased in diabetes reducing the levels of NADPH which is an essential cofactor for NO synthesase & increase levels of calcium elevating messengers, thus increasing smooth muscle contractility.

• Decreased endothelium –derived hyperpolarization factor(EDHF) in human penile arteries,hence reduction of endothelium-dependent relaxation

M.Y.A.Mawla 60

Hyperglycemia in DM

• Associated with diminished biologic actions of NO• Tesfamariam: impaired vasodilatory responses to

high glucose levels--caused by increased oxygen-derived free radicals through a protein kinase C-mediated mechanism that stimulates the formation of vasoconstrictor prostanoids

• The vasoconstrictor effect can be abolished by aldose reductase inhibitors

• High glucose increase both NO synthase expression & superoxide anion generation by aortic endothelial cells.

M.Y.A.Mawla 61

Dyslipidemia in DM (1)• Elevated TG, low HDL-c, and elevated IDL—

insulin resistance syndrome• Hypercholesterolemia is associated with impaired

endothelium-dependent vasodilation in human forearm & pig coronary arteries & rabbit aorta

• These functional vascular changes associated with Increase generation of ROS Persistence of endothelial NO release Increased generation of OONO- Oxidative modification of LDL

M.Y.A.Mawla 62

Dyslipidemia in DM (2)

• The extent of ROS formation-also be a determinant of endothelial NO release-it may affect the proportion of circulating and tissue cholesterol that has been oxidized

• Oxidatively modified LDL--impair endothelium-dependent vasodialtion more than native LDL in vascular ring

• Hypertriglyceridemia-independent risk factor for CAD • Postprandial hypertriglyceridemia--cause a transient impairment of

endothelium-dependent vasodilation in normal volunteers• Postprandial hypertriglyceridemia is more exaggerated in type 2

diabetics & associated with higher forearm venous free radical & greater impairment of flow-dependent vasodilation

M.Y.A.Mawla 63

Increased oxidative stress in diabetes

• Oxidative stress—imbalance between the production of ROS and the numerous antioxidant defense mechanisms present in biologic systems

• Reactive oxygen species (ROS) include superoxide anion that is converted to hydrogen peroxide both enzymatically and by several isoforms of the enzyme superoxide dismutase

• In diabetes, overproduction of ROS overwhelms normal antioxidant defenses with consequent alterations in both the function and the structure of the CV system

M.Y.A.Mawla 64

Insulin resistance syndrome and endothelial dysfunction

• Syndrome of insulin resistance may precede the onset of overt type 2 diabetes

• The clinical features include hyperinsulinemia, truncal obesity, hypertension, and dyslipidemia characterized by elevated serum TG, low HDL-C, and increased IDL

• These hallmarks are thought to result from relative insensitivity of selected tissues, particularly skeletal muscle, to the action of insulin

M.Y.A.Mawla 65

Insulin resistance syndrome• It is hypothesized that compensatory

hyperinsulinemia maintains the serum glucose within the normal range until pancreatic islet -cells can no longer produce sufficient insulin, and overt type 2 diabetes occur

• Insulin resistance is associated with a clustering of CV risk factors that predispose patients with this metabolic syndrome to later CV events

• There is evidence of sympathetic nervous system activation that may contribute to the hypertension that develops.

M.Y.A.Mawla 66

Insulin resistance syndrome• Insulin itself promotes vasodilation, in part

through stimulation of endothelial NO release

• This vasodilatory action may be counterbalanced in the insulin resistance syndrome by the development of hypertension, which independently impairs endothelium-dependent vasodilation

M.Y.A.Mawla 67

Endothelin and endothelial dysfunction in diabetes

• Endothelin-1, a 21-amino-acid peptide, is the predominant isoform of the endothelin peptide family that includes ET-2, ET-3, and ET-4

• Endothelin-1 is produced primarily by endothelial cells but can also be synthesized by vascular smooth muscle cells (VSMCs) and by macrophages

• The action of ET-1 are mediated by 2 receptor subtypes, ETA and ETB receptors

Endothelin in DMEndothelin in DM

• Plasma ET-1 are increased in type 2 diabetes• Most of the ET-1 cause vasoconstriction of VSMCs

through a paracrine effect mediated by ETA receptors

• Infusion of ET-1 cause sustained increases in BP • Nonselective ETA/ETB antagonist, bosentan, lowers

BP in patients with essential hypertension• Plasma ET-1-may be a marker for atherosclerotic

disease in type 2 diabetic patients• ET-1 participate in the fibrotic process--an essential

component of the glomerulosclerosis, cardiac and vascular remodling, and atherosclerosis that occur at an accelerated rate in hypertensive type 2 diabetics.

Advanced glycation end products Advanced glycation end products (AGEs)in Diabetes(AGEs)in Diabetes

• AGEs formed by the nonenzymatic binding of glucose to lipids or to free amino groups on proteins

• The formation of AGEs is inhibited by NO, whose biologic actions are blunted in diabetics

• The increased stiffness of the arterial wall contributes to isolated hypertension

• The increased systolic pressure in turn produces an increased workload on the left ventricle, resulting in increased left ventricular mass

• Reduction arterial wall compliance linked to increased CV risk in type 1 & 2 diabetics and occur early in the course of DM before vascular disease is clinically apparent

Adverse consequences associated with Adverse consequences associated with endothelial dysfunction in diabetes mellitusendothelial dysfunction in diabetes mellitus

• Decreased NO formation, release, and action• Increased formation of reactive oxygen species• Decreased prostacyclin formation and release• Increased formation of vasoconstrictor prostanoid• Increased formation and release of ET-1• Increased lipid oxidation• Increased cytokine and growth factor production• Increased adhesion molecule expression• Hypertension• Changes in heart and vessel wall structure• Acceleration of the atherosclerotic process

HYPERTENSION and Risk of HYPERTENSION and Risk of Endothelium & Erectile DysfuctionEndothelium & Erectile Dysfuction

• CVS complications of hypertension is associated wit ED.

• In ED due to arterial insufficiency: low oxygen tensionin corporal blood,reduced PGE1 &PGE2, Increased tranformation of transforming growth factor(TGF)-B-induced fibrillar collagen synthesis in corpus cavernosa.

• Diffused venous leakage & failure of veno-occlusive mechanisms.

• Endothelial –dependent vasodilation:impaired.

• Age dependent &independent decrease of NO synthesis.

Proposed vascular pathophysiology in Hypertension

Vaughan CJ, Delanty N. Lancet. 2000;356:411-7.Courtesy of JJ Ferguson III, MD.

Acute ↑ BP triggers ↑ cellular adhesion molecular expression

NO

PGI2

CatecholaminesAT-II

ADH (vasopressin)Aldosterone

TxA2

ET1( - ) ( + )

CAMs

Endogenous vasodilators

Endogenous vasoconstrictors

Endothelium in HypertensionEndothelium in Hypertension

Endothelial mechanoreceptors Endothelial mechanoreceptors changes in hypertension –induced changes in hypertension –induced

stressstress

Cigarette SmokingCigarette Smoking

• Free radicles&aromatic compounds released from cigarette smoke: decrease endothelial NO Synthesae activity and elicit superoxide –mediated NO degradation ,tending to increased penilemisculature & promoting ED.

• Direct toxic effects of nicotine & CO2 on penile vasculature.

• Increased hyper- coaglulability agents

ATHEROSCLEOSIS & ATHEROSCLEOSIS & HYPERLIPIDEMIA :Effect on penile HYPERLIPIDEMIA :Effect on penile

endotheliumendothelium• Chronic ischaemia:reduced NOS activity,reduced

enothelium-dependent & neurogenic NO-mediated relaxation of cavernosal tissue together with elevated thromboxane-mediated contractions.

• High LDL : elevated contraction due to increased intracellular inositol & calcium.

• Chronic hypercholestraemia:1. Reduced endothelium dependent relaxation in

cavernous tissue.2.Impaired NO/cGMP pathway due to elevated

superoxides & NOS inhibitors (eg.nitromonomethyl l arginine L_NMMA).

M.Y.A.Mawla 76

Can We MeasureEndothelial Function ??

M.Y.A.Mawla 77

Clinical Methods for Assessing Endothelium - Dependent Dilation

Forearm• Brachial Artery Diameter with Arterial Occlusion FMD• Forearm Blood Flow with ACh

M.Y.A.Mawla 78

M.Y.A.Mawla 79

Penile/Brachial Index (PBI)

•0.7 - 1.0 = normal

•0.6 - 0.7 = borderline abnormal

• <0.6 = abnormal

M.Y.A.Mawla 80

What is the Treatment. for Endothelial Dysfunction ??

M.Y.A.Mawla 81

• Control of all the known CV risk factors• Main focus on the big six – DM, HTN, Lipids,

Obesity, Smoking, Sedentary life style• Diet and physical activity are vital in Rx of ED• Statins are the first line treatment for ED• Insulin and Rx. Insulin resistance improves

ED

What is the Treatment for Endothelial Dysfunction?

M.Y.A.Mawla 82

Erectile Dysfunction – Today’s concept

Penis is the barometer of Endothelial Health

Erectile Dysfunction is amirror of Cardiovascular Risk

ED = ED

M.Y.A.Mawla 83

Endothelial Dysfunction

DILATATIONNitric Oxide

1. Prostaglandin E1 &cAMP pathway

Constriction•Endothelin peptides

•Angiotensin•Prostacyclins

•Rho A/RhoA-kinase

Age

Family history

Smoking

Hypertension

Low HDL-C

High LDL-C

Diabetes Mellitus

M.Y.A.Mawla 84

Targeting Endothelium Dysfunction in Erectile

Dysfunction• Treating risk factors &disorders.• Cessation of smoking.• Long term phosohodiesterase-5 inhibitors

therapy• Antioxidant therapy• Future directions

1. Corporal tissue engeneering

2. Gene therapy(eg Rho A/Rho A-kinase antisense gene therapy).

M.Y.A.Mawla 85

M.Y.A.Mawla 86

Type 5 Phosphodiesterase (PDE5) Inhibitors

• Viagra (Sildenafil) Tabs: 25, 50, 100 mg.

• Levitra (Vardenafil) Tabs: 2.5, 5, 10, 20 mg.

• Cialis (Tadalafil) Tabs: 5, 10, 20 mg.

M.Y.A.Mawla 87

Take Home Messages

• Common under laying pathology is ED& ED.

• Endothelial Dysfunction can be measured• Endothelium is the largest endocrine gland• ED is diagnostic and prognostic• ED can be treated and monitored• ED = ED – So careful evaluation is needed• Penis is the barometer of CV Risk

M.Y.A.Mawla 88

THANK YOU