Endothelial Dysfunction in Erectile Dysfunction: Role of the Endothelium in Erectile Physiology and Disease

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual intercourse. Basic science research on erectile physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin. The incidence of ED dramatically increases in men with diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED in this cohort of men. This communication reviews the role of the vascular endothelium in erectile physiology and the influence of endothelial dysfunction in the pathogenesis of ED. Future pharmacological and gene therapy interventions to restore endothelial function may represent exciting new therapeutic strategies for the treatment of ED. Penile erection is a neurovascular phenomenon that depends upon neural integrity, a functional vascular system, and healthy cavernosal tissues (Giuliano et al, 1995). Normal erectile function involves 3 synergistic and simultaneous processes: 1) neurologically mediated increase in penile arterial inflow, 2) relaxation of cavernosal smooth muscle, and 3) restriction of venous outflow from the penis. The corpus cavernosum of the penis is composed of a meshwork of interconnected smooth muscle cells lined by vascular endothelium. Of note, endothelial cells and underlying smooth muscle also line the small resistance helicine arteries that supply blood to the corpus cavernosum during penile tumescence. Pathological alteration in the anatomy of the penile vasculature or impairment of any combination of neurovascular processes can result in ED. Aging is most commonly associated with ED, but a number of underlying disease processes are recognized to lead to abnormal function and responsiveness of the penile vascular bed. ED was believed to be a psychological condition; however, in the past 2 decades, recognized that the of erectile can be to an ED may result from or cavernosal and is associated with vascular as hypercholesterolemia, diabetes mellitus, and et al, et al, ED is in men with cardiovascular and cardiovascular disease is to be associated with endothelial can that endothelial dysfunction of the penile vascular may to in erectile has been that endothelial dysfunction can result in ED et al, et al, and science on hypercholesterolemia, and that endothelial dysfunction is a to penile vascular The the role of the vascular endothelium in erectile physiology and the of the endothelium in erectile physiology and in endothelial function can on erectile The vascular endothelium as a for the arterial and venous but also plays a role in vascular and blood in to and and the role of the endothelium in and of is that the vascular endothelium has a role in the of vascular in the by a of that the and of the underlying vascular smooth The of the endothelium are to vascular also a role in the of vascular smooth muscle and and The endothelium to and as as to by in blood and by that the of the underlying smooth muscle disease of the functional integrity of the vascular endothelium plays an integral role in the of the endothelium to to and and a to as endothelial dysfunction and and The role of the endothelium during endothelial is a in responsiveness to or an increase in to dysfunction to and of vascular and of vascular and the endothelial dysfunction is most commonly to to in smooth muscle relaxation by a of or of in the The in in endothelial dysfunction may be by in the endothelial a of or for in that is or or of by as in endothelial to the are that dysfunction from abnormal or from the endothelial is that as may be from the This a in the of the the role of and the role of vascular processes are the of from the vascular smooth muscle and et al, has of vascular and and penile erection et al, to has been to an on smooth muscle and The of and from in most tissues of the The that this in cells and is This and as and as a The of the and are to and and are the in the of penile erection et al, et al, et al, is of and and new et al, is predominately is to the of and is also to the muscle et al, The of are the vascular and are predominately by The and are predominately the is in to an or and 1995). the of to of the with the and the of and of the been to an integral in the of et al, and et al, et al, et al, by 1) from endothelial cells the cavernosal smooth muscle cells and resistance helicine arteries in to 2) by from and 3) in is in that and penile vascular The most of in the penis is the of et al, to smooth muscle cells This to a increase in smooth muscle is the by and to of the smooth muscle et al, can also to or lead to an alteration of the of the et al, and and of The smooth muscle relaxation in of blood and of the corpus cavernosum and penile The of are by the of the by the The of the in the erectile was in et al, are to and cavernosal smooth muscle relaxation in to and endothelial and the defined role of and in the of penile erection has been a of the for and to erectile function and et al, The for the of the erectile in was a of to for the erectile in is the of gene from of the and in et al, erectile function to of the cavernosal of the with et al, Of from for the of in penile the of and of the endothelium in cavernosal smooth muscle relaxation and erection et al, with of the and the role of on the of penile erection and of the of of penile from in the the penis is for the of cavernosal smooth muscle relaxation and subsequent The of from in the endothelial cells of the corpus cavernosum and arteries the penis has been and for in the of the corpus cavernosum and in the small resistance helicine arteries of the penis et al, et al, et al, et al, et al, et al, and that the corpus cavernosum is of in the of and impairment of cavernosal smooth muscle relaxation in in as diabetes mellitus, and et al, et al, et al, role in the of penile erection in the past has been the role of from in the of penile erection in physiology and in disease on the for and of penile erection is that penile erection is by neural the and increases the of from an increase in blood to the cavernosal et al, is by a by blood from the arteries the and of the of the The on the endothelial of the smooth muscle cells and arteries to the of penile erection of the of and in the and of the erectile from et al, and pharmacological and that penile processes to cavernosal and relaxation of the corpus cavernosum are mediated by and of the This to increase et al, The of pharmacological of in the penis of and that to to and This was to be for a of with subsequent increases in and of erection The of in the erectile has to the in the of as and the and diabetes impairment in erectile function that is to in the and in the as as the in neural integrity of the cavernosal and as as in endothelial function are ED associated with is but most that is an in et al, et al, the role of in disease processes was gene of to the corpus was that this was of erectile function in and with diabetes of et al, et al, and et al, in that in disease in is or of this is of erectile function to cavernosal and cavernosal gene therapy has on or gene in that of erectile function is upon and the of in the of the erectile and in associated with ED and endothelial number of the and of penile erection et al, The an of the and in the physiology of penile smooth muscle cells in the penis are predominately in the with blood the The and and the of smooth muscle of the penis This is by and and involves a of cells vascular and vascular in and by to and with the of a of and the corpus the vascular endothelium and cavernosal arteries are a of as the and the and a influence on cavernosal vascular in to an on cavernosal smooth muscle is in to in blood and in to maintain the penile vascular bed. The of and is during and to in blood and in and been to be in cardiovascular to endothelial and increases in to and also been et al, to that this also in the penile vascular bed. The of cavernosal smooth muscle relaxation is by the the penis and by cavernosal endothelial cells 1995). is from endothelial cells the influence of as from in the and as by blood in the of the corpus cavernosum et al, to the underlying smooth muscle cells the of of and the of The and cavernosal smooth muscle relaxation can in blood in the to cavernosal smooth muscle relaxation is of a et al, The and are by endothelial cells in the is the most in vascular tissues et al, of and can to is to by the of and by by endothelial cells in the corpus cavernosum in to blood in the penis to on smooth muscle cells et al, et al, of by increases of of a in of and cavernosal smooth muscle relaxation et al, and are in corpus cavernosum smooth are and are in the corpus cavernosum et al, and are and are for an increase in in to to the penis and in cavernosal smooth muscle is a of the penile vascular and is a for the treatment of ED et al, The plays an role in erectile is by or and the underlying relaxation by of the smooth muscle cells et al, This involves the of the and the of increase as the and was believed that the to smooth muscle by the of on the smooth muscle however, this has been in of that is an increase in endothelial by an or that the of a is for the subsequent et al, is an of that to an role in the of vascular et al, are to be in a number of vascular of and arteries by smooth muscle cells a and et al, the role of cavernosal smooth muscle relaxation has been et that an relaxation of penile resistance arteries is to and that may an role in the relaxation of the penile vascular bed. has that the pharmacological of cavernosal mediated erectile in the This that a may an smooth muscle in the penis that may to the erectile this of penile vascular is research be to the of this in the of penile the erectile cavernosal the for in and of the in a of The in erectile was and of number of from is a to the is a functional that in the vascular of the penis et al, in the penile vasculature that endothelial cells in the corpus cavernosum may a that may vascular by the cavernosal smooth muscle cells in a et al, of of corpus a of the cavernosal in et al, of been in men with ED, this may a role in the pathogenesis of ED et al, The and are a of is a in the vascular endothelium that is recognized as a and in the penile vasculature et al, et al, The of are mediated are on the underlying smooth muscle, and are on the smooth muscle and vascular endothelium. and of smooth on smooth muscle also of on the endothelium and Of note, as a and as a to cavernosal in of by endothelial cells of the corpus cavernosum is to to cavernosal smooth muscle and of penile and this the of in the most and a role for in the erectile et al, et al, et al, corpus cavernosum from and that are and are that may be in the pathogenesis of ED et al, et al, are to the functional of cavernosal in the of endothelial is a for the of and This is from the cells by as are cells the This is mediated by the is composed of and The of has been in the but is The of is the in the is to and by the tissues and also the in endothelial cells et al, the endothelial and can with the or with and is can to the of to with and are can with to that to or with to can in endothelial is as a by and and as a may by with for is to be to the of et al, et al, in 2 the and the and has that endothelial cells from the corpus cavernosum et al, by and been in the corpus cavernosum et al, of with is associated with and of corpus cavernosum smooth muscle, that of increase a et al, is to in endothelial and smooth muscle cells of the penis by the of to with and of the can has been to be in corpus that the erectile by in men with diabetes may be to a combination of of and of on and the of is also a of the of to and can be in that and the of of in endothelial cells the of and and diabetes and may influence in the penis and to endothelial dysfunction in the in the of the of the penile vascular by has been the in the of the are of cavernosal smooth muscle is mediated by the of in the of and subsequent has the role of the of or the of et al, of is the from vascular that a of the of of and et al, The of for on and of from the to the are of and the of as an role for and in the of smooth muscle cells et al, et al, and the in vascular smooth muscle and may a the role of has been in of smooth muscle, has in the of cavernosal smooth muscle et al, et al, et al, endothelial cells and corpus cavernosum smooth muscle cells in and et al, et al, et al, and and with in the penile vascular bed. is by or vascular disease and to the in and and the of This in cavernosal smooth muscle 2 of is in the the of and cavernosal smooth muscle This the of the system, to the and This in an increase in and and cavernosal smooth muscle relaxation 2 of and the role of in the of cavernosal smooth muscle has been by of the the cavernosal of increase in et al, gene of the to the corpus cavernosum erectile that of in the penis can cavernosal smooth muscle relaxation and subsequent erectile function et al, with also increases in erectile and of or this et al, by and that and can the of to the in the was to the of in the is of on and the the erectile in of the that the that may the of that the is an of penile vascular endothelial function et al, The plays an role in of gene and in endothelial in This may an role in the of penile endothelial function and dysfunction as to vascular of the penile vasculature on and are a of by of as a result of of or This phenomenon is commonly to as and are as the and and are by but that to in as the vascular endothelium. cells in to and in vascular disease of the most in the vasculature is is in a of vascular smooth muscle and endothelial cells et al, et al, most endothelial the to et al, of in endothelial cells and and The of and in the vascular endothelium or smooth muscle cells in the of the is to in vascular of and and dysfunction et al, and This is that of and and 3 the of this is with cells and the The and an role in the and a and by the of and et al, been a a and an is also a is to a role in the of the vascular and the of in the the endothelial and smooth muscle cells et al, the and been in the predominately in the endothelial and cavernosal smooth muscle cells et al, an of in the endothelium and cavernosal smooth muscle may to ED by penile and endothelial dysfunction as commonly in the vascular of hypercholesterolemia, and This is an cavernosal smooth muscle relaxation and penile erection upon the of by a healthy endothelium. of in the of and as an in the of endothelial dysfunction in vascular as and vascular are in with ED and been as for ED in of by in of an that to a of and of endothelial can in the vasculature the of 3 and a number of may lead to in penile erection et al, can of in the cavernosal endothelial an of to of and of endothelial may to in the penile vasculature in ED associated with to increase and The of on the role of on corpus cavernosal and endothelial function in the penis has been in The of a on in cavernosal smooth muscle relaxation that relaxation was in the corpus cavernosum in the of of that can in erectile et al, the of and erectile in and in has been in of ED. is that in in corpus cavernosal smooth muscle in corpus cavernosal endothelial smooth muscle relaxation a cavernosal in the et al, was a increase in cavernosal and in to the as a result of of the in smooth muscle to the of and to endothelial cells a role in the of et al, is an by and and associated with and has been to relaxation in the penis and may also to endothelial dysfunction in an of of or a in the et al, are to the in a of endothelial dysfunction of the penile vascular associated with and and that and to ED. in and cavernosal smooth muscle relaxation are in corpus cavernosum in and in et al, et al, et al, and et al, et al, et al, that may a role in endothelial dysfunction of the penile vascular bed. cavernosal smooth muscle relaxation is in with cavernosal et al, treatment and corpus cavernosum smooth muscle the functional of in endothelial dysfunction in et that a that is a of is in cavernosal from with has a of by the in cavernosal of with diabetes with in et al, ED as by cavernosal erectile in gene of to the penis the increase in cavernosal and cavernosal erectile function in this cohort of et al, that an increase in by an of a increase in in the penis of the with diabetes and that gene therapy of can and restore erectile function in that in diabetes are by the of and to endothelial dysfunction of the penile vasculature in Aging is associated with in the in the endothelium and smooth muscle cells and is an to vascular dysfunction in et al, et al, are in the cardiovascular and a number of vascular with endothelial dysfunction of the penis may as or in Aging is associated with and responsiveness to in the corpus and the role plays in this responsiveness been with to this to role in and penile the of of and endothelial cells in the erectile et al, et al, may be a result of of in the penis. in of was to be in endothelial and cavernosal smooth muscle cells of the et al, was an increase in was in that was an in and in the penile vasculature of the This increase in is associated with in the smooth muscle relaxation and in erectile function et al, was this in and that led to that be in with of and was and in a in in the penis. gene therapy and in the penile vasculature that was associated with in erectile to cavernosal and the in the et al, a role for in erectile function in by of and endothelial function in the penis. of in and of and with is to cells in the of is to is by with This of in of in the and small of the and corpus cavernosal smooth is a increase in in the small and corpus cavernosal smooth corpus cavernosum smooth and subsequent are for the of ED et al, is to that endothelial dysfunction and subsequent ED in men are and are by vascular as and The of and ED was to of the cavernosal arterial that in a in arterial to the penis and et al, the of cavernosal smooth muscle relaxation has in to a in endothelial and smooth muscle cells with of in the corpus cavernosum as as and of the penis et al, et al, of the arteries in and processes in of the cavernosal et al, of hypercholesterolemia, in in relaxation to in the corpus cavernosum is and relaxation to may be or and et al, is in cavernosal from with hypercholesterolemia, and is et al, with hypercholesterolemia, erectile function was to in as as in and of corpus cavernosum in et al, in smooth muscle relaxation and in the penis as a result of hypercholesterolemia, the of in the of erectile endothelial is an endothelial in and an in and et al, in corpus cavernosal smooth muscle cells and an increase in of in endothelial cells in et al, penile erection in a of ED by of and that erection et al, The of gene therapy to endothelial function in the penis of has been and of endothelial and smooth muscle relaxation of the corpus cavernosum et al, et al, et al, that can in smooth muscle relaxation of the corpus cavernosum of Future are to gene therapy can endothelial dysfunction of the penile vascular and are and this therapy can erectile function in vascular disease and of are associated with diabetes in the vasculature may the of ED in men and to ED in is a in the number of and and smooth muscle relaxation et al, et al, et al, that with and diabetes in penile and and cavernosal a in erectile function to cavernosal and erectile and are et al, et al, and et al, et al, et al, et al, to be and of in penile of with may be a to increase et al, cavernosal smooth muscle relaxation is also in of that diabetes and but may also smooth muscle and the or and a for the of ED in diabetes that is a of the with a in a in and in the penile smooth muscle relaxation is in of the for and restore smooth muscle of to with diabetes smooth muscle treatment restore that or to with in the endothelium is to endothelial dysfunction in et al, The with for the in endothelial cells the vascular of in corpus cavernosum may by that and and gene in corpus cavernosum with cavernosal et al, cavernosal a of to that the by predominately is in the of the of to was in cavernosal may that the by the for and that of by the of to in of the to in endothelial function dramatically erectile function in in gene of on penile erection in a that is associated with endothelial dysfunction and the with diabetes to the of gene of on erectile in this and et al, in that diabetes in cavernosal and in erectile to of and cavernosal gene of to the an increase in cavernosal and was in the corpus cavernosum that in a of erectile function to cavernosal and erectile to et al, in that gene of to the corpus cavernosum erectile the increase in in to of the in and with diabetes with or erection 2 with with diabetes in erectile to the of endothelial dysfunction of the penile vascular bed. gene therapy with erectile to number of with with with diabetes with The of with the been The role of in endothelial dysfunction from with and endothelial function by of and restore and gene and of by the to increases in and in et al, that an role in of gene and in endothelial to a of vascular dysfunction et al, this may to of the of smooth muscle relaxation in endothelial The role of in the pathogenesis of ED has been et that is in corpus cavernosum from with with diabetes also an increase in and in corpus cavernosum a and is et al, This increase in was associated with in erectile to the but a in erectile to cavernosal that the erectile in the with diabetes may be to as a result of as in vascular to this the penis of the with diabetes an for a to in the corpus gene of the erectile to cavernosal to the and was et al, and with in that in of is an of cavernosal as a result of in the penis. a that may an role in the pathogenesis of endothelial and ED in is the of and 2 is to to on or a of and are and in tissues in endothelial and vascular smooth muscle cells et al, during the is in diabetes as a of an increase in et al, 1995). of is the of to vascular with of endothelial and of the vascular are to in and is associated with in endothelial and smooth muscle cells and of and of been to by of the to and alteration of et al, are in cavernosal with that may be in the pathogenesis of endothelial and ED et al, of of can in cavernosal smooth muscle relaxation and in erectile to cavernosal by of of and in the penile vasculature et al, et al, in the of erectile in with diabetes et al, The of on erectile physiology are to this pharmacological is also an of may in the of the of the the arterial to the penis. the of to be in the pathogenesis of endothelial dysfunction as to The penile vascular the arterial and vascular that endothelial The underlying vascular endothelial dysfunction however, the of ED is an and and relaxation of the penile vascular Aging is recognized to endothelial and the in erectile function and erectile to has been to in in the smooth muscle and or of et al, et al, et al, et al, The endothelial dysfunction in the penis is to a in Normal and of been in the corpus cavernosum from a number of et al, The of in the corpus cavernosum is a result of of and in of and of a et al, et al, and endothelial are in the and et al, endothelial dysfunction and in the penis are in mediated by an increase in of and of in the penile as by of to in and cavernosal with and cavernosal a in is a of gene therapy with was to in number of with with cavernosal with or in has been in the penis et al, This in is to to erectile to cavernosal and penile in the role of and to endothelial function and erectile function in was gene was to an that the to the penis of gene of in an of and cavernosal et al, et al, was in The result of of in the penis was a in erectile was an increase in erectile function as by cavernosal and an in endothelial function in that erectile gene that the has in the penis and can the endothelial dysfunction and ED associated with a of from the vascular endothelium of the penis. for the of but in and in the penis may be a with for The can in the vascular is in may also be in the of in endothelial in the penis and to this endothelial cells from and and and that and and are in cavernosal endothelial cells in as as corpus cavernosum from the et al, pharmacological of and an for an to that by and in in endothelial cells restore et al, gene of the for erectile to and cavernosal erectile and in the penis et al, This that with and function of increases in the penile vascular and to endothelial dysfunction and ED as to that may be a as to in the treatment of ED in with and of are of to with and or has been to and The of endothelial cells is by the of The in a of and or upon are associated with dysfunction of the vascular endothelium in a number of vascular and of but in with are to et al, are associated with in with hypercholesterolemia, that this endothelial function et al, of in in blood et al, been to be of in with disease and diabetes et al, that may be a of endothelial dysfunction as to cardiovascular but may also endothelial dysfunction associated with vascular for the of or in the pathogenesis of endothelial dysfunction as to ED been of cavernosal that in corpus cavernosum was associated with and of and et al, of in this Future in associated with endothelial dysfunction and ED hypercholesterolemia, to be in to an of of and cavernosal endothelial function in the penis. The endothelium plays a role in vascular in the penis. plays an integral role in the physiology of erection in and in disease The in vascular disease associated with ED are of the a in that the of the is that that endothelial as cardiovascular and hypercholesterolemia, are associated with ED. penile erection arterial and smooth muscle of the in endothelial dysfunction as to vascular of the penis lead to strategies and pharmacological or gene for ED. to for in the of the and and for with the and for with the of the This was in by a from the for and and The for Aging