madman
Super Moderator
Abstract
A diagnostic of hypertension increases the risk of erectile dysfunction (ED); likewise, ED can be an early sign of hypertension. In both cases, there is evidence that endothelial dysfunction is a common link between the two conditions. During hypertension, the sustained and widespread release of procontractile factors (e.g., angiotensin II, endothelin 1, aldosterone) impairs the balance between vasoconstrictors and vasodilators and, in turn, detrimentally impacts vascular and erectile structures. This pro-hypertensive state associates with an enhancement in the generation of reactive oxygen species, which is not compensated by internal antioxidant mechanisms. Recently, the innate immune system, mainly via Toll-like receptor 4, has also been shown to actively contribute to the pathophysiology of hypertension and ED not only by inducing oxidative stress but also by sustaining a low-grade inflammatory state. Furthermore, some drugs used to treat hypertension can cause ED and, consequently, reduce compliance with the prescribed pharmacotherapy. To break down these challenges, in this review, we focus on discussing the well-established as well as the emerging mechanisms linking hypertension and ED with an emphasis on the signaling network of the vasculature and corpora cavernosa, the vascular-like structure of the penis.
DISCUSSION
ED, defined as the persistent inability to attain and/or maintain an erection for satisfactory sexual intercourse9, has a 50% prevalence after the age of 40 in the general population10, and it is exacerbated during hypertension11. High blood pressure affects the blood flow to the penis, a crucial step in the process of achieving and keeping an erection12,13. Therefore, it is not surprising that ED is a significant problem in hypertensive men. The interaction between high blood pressure and ED is not simple as ED can be diagnosed as an early marker or as a secondary complication of hypertension14 (Figure 1). Such an intricate relationship mainly occurs because of alterations in the endothelium, which affects smooth muscle tone and contributes to the development and maintenance of both conditions.
Vasoconstrictors: the pro-contractile challenges
The pathophysiology of hypertension strongly associates with an increase in the release of vasoconstrictors, especially angiotensin II (AngII), endothelin 1 (ET-1), and aldosterone. Herein, we highlight the specific contributions of these molecules, as their sustained release poses a significant challenge to the endothelial cells lining the inner wall of blood vessels and the blood-filled sinuses of the corpus cavernosum. The resulting endothelial dysfunction not only leads to but also sustains a procontractile state in the vasculature and vascular-like structures, a hallmark of hypertension, and ED.
A. Angiotensin II
B. Endothelin 1
C. Aldosterone
Vasodilators: the pro-relaxation challenges
A major challenge encountered by the vasculature and vascular-like structure of the penis under hypertension, besides upregulation of vasoconstrictors, is the reduction in the availability of prorelaxation factors, such as the gaseous transmitters NO and hydrogen sulfide (H2S), which highlights these molecules as wells as their downstream pathways as potential common targets for hypertension and ED. Also, during hypertension mechanisms that should be activated to counterbalance the proconstriction state, including stimulation of the angiotensin (1-7)/Mas receptor axis and the redox-sensitive transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2), are compromised as they elicit, in most cases, an inefficient response.
A. Nitric oxide
B. Hydrogen sulfide
C. Angiotensin (1,7)
D. Nrf2
*Vascular senescence: more than a chronological challenge for hypertensive patients
*Antihypertensive drugs: a double-edged sword challenge
*Immune system activation: a missing challenge for hypertension and ED
Final considerations
As discussed in this review, a dysfunctional endothelium plays a prominent role in the pathogenesis and pathophysiology of hypertension and ED. A continuous increase in the release of vasoconstrictors (e.g., AngII, ET-1, and aldosterone) leads to endothelial dysfunction, which affects not only the vasculature but also the corpus cavernosum. In penile tissue, endothelial dysfunction is a hallmark for the development of ED, which can be an early sign of systemic vascular disease, including hypertension. On the other hand, persistent alterations in the vascular system precede hypertension, a significant risk factor for ED. In Figure 2, we highlight pathways shared by hypertension and ED via the vasculature and vascular-like structures of the penis. An interesting aspect of this figure is the clear emergence of ROS as a hub, which reaffirms that oxidative stress is a pathological mechanism with a negative impact on vascular and erectile structures.
It is noteworthy that while we gathered a consistent body of evidence pointing to endothelial dysfunction, substantiated by the increased release of vasoconstrictors and reduced availability of vasodilators, as a common challenge for hypertension and ED, there is, still, much to be understood regarding the overlapping pathways of these conditions. Over the last decade, it is becoming widely accepted that the innate immune system contributes to the pathophysiology of vascular-related diseases. The literature consistently shows that targeting these receptors, mainly TLR4, improves vascular and erectile function. However, while it seems that the receptors of innate immunity impact the disease progression, we are only now uncovering their part in hypertension and ED. Such contributions to our understanding shift the way we are approaching these diseases, and ultimately, will open research avenues for the development of new therapeutics, that hopefully, will be more effective in the management of both conditions.
A diagnostic of hypertension increases the risk of erectile dysfunction (ED); likewise, ED can be an early sign of hypertension. In both cases, there is evidence that endothelial dysfunction is a common link between the two conditions. During hypertension, the sustained and widespread release of procontractile factors (e.g., angiotensin II, endothelin 1, aldosterone) impairs the balance between vasoconstrictors and vasodilators and, in turn, detrimentally impacts vascular and erectile structures. This pro-hypertensive state associates with an enhancement in the generation of reactive oxygen species, which is not compensated by internal antioxidant mechanisms. Recently, the innate immune system, mainly via Toll-like receptor 4, has also been shown to actively contribute to the pathophysiology of hypertension and ED not only by inducing oxidative stress but also by sustaining a low-grade inflammatory state. Furthermore, some drugs used to treat hypertension can cause ED and, consequently, reduce compliance with the prescribed pharmacotherapy. To break down these challenges, in this review, we focus on discussing the well-established as well as the emerging mechanisms linking hypertension and ED with an emphasis on the signaling network of the vasculature and corpora cavernosa, the vascular-like structure of the penis.
DISCUSSION
ED, defined as the persistent inability to attain and/or maintain an erection for satisfactory sexual intercourse9, has a 50% prevalence after the age of 40 in the general population10, and it is exacerbated during hypertension11. High blood pressure affects the blood flow to the penis, a crucial step in the process of achieving and keeping an erection12,13. Therefore, it is not surprising that ED is a significant problem in hypertensive men. The interaction between high blood pressure and ED is not simple as ED can be diagnosed as an early marker or as a secondary complication of hypertension14 (Figure 1). Such an intricate relationship mainly occurs because of alterations in the endothelium, which affects smooth muscle tone and contributes to the development and maintenance of both conditions.
Vasoconstrictors: the pro-contractile challenges
The pathophysiology of hypertension strongly associates with an increase in the release of vasoconstrictors, especially angiotensin II (AngII), endothelin 1 (ET-1), and aldosterone. Herein, we highlight the specific contributions of these molecules, as their sustained release poses a significant challenge to the endothelial cells lining the inner wall of blood vessels and the blood-filled sinuses of the corpus cavernosum. The resulting endothelial dysfunction not only leads to but also sustains a procontractile state in the vasculature and vascular-like structures, a hallmark of hypertension, and ED.
A. Angiotensin II
B. Endothelin 1
C. Aldosterone
Vasodilators: the pro-relaxation challenges
A major challenge encountered by the vasculature and vascular-like structure of the penis under hypertension, besides upregulation of vasoconstrictors, is the reduction in the availability of prorelaxation factors, such as the gaseous transmitters NO and hydrogen sulfide (H2S), which highlights these molecules as wells as their downstream pathways as potential common targets for hypertension and ED. Also, during hypertension mechanisms that should be activated to counterbalance the proconstriction state, including stimulation of the angiotensin (1-7)/Mas receptor axis and the redox-sensitive transcriptional factor nuclear factor erythroid 2-related factor 2 (Nrf2), are compromised as they elicit, in most cases, an inefficient response.
A. Nitric oxide
B. Hydrogen sulfide
C. Angiotensin (1,7)
D. Nrf2
*Vascular senescence: more than a chronological challenge for hypertensive patients
*Antihypertensive drugs: a double-edged sword challenge
*Immune system activation: a missing challenge for hypertension and ED
Final considerations
As discussed in this review, a dysfunctional endothelium plays a prominent role in the pathogenesis and pathophysiology of hypertension and ED. A continuous increase in the release of vasoconstrictors (e.g., AngII, ET-1, and aldosterone) leads to endothelial dysfunction, which affects not only the vasculature but also the corpus cavernosum. In penile tissue, endothelial dysfunction is a hallmark for the development of ED, which can be an early sign of systemic vascular disease, including hypertension. On the other hand, persistent alterations in the vascular system precede hypertension, a significant risk factor for ED. In Figure 2, we highlight pathways shared by hypertension and ED via the vasculature and vascular-like structures of the penis. An interesting aspect of this figure is the clear emergence of ROS as a hub, which reaffirms that oxidative stress is a pathological mechanism with a negative impact on vascular and erectile structures.
It is noteworthy that while we gathered a consistent body of evidence pointing to endothelial dysfunction, substantiated by the increased release of vasoconstrictors and reduced availability of vasodilators, as a common challenge for hypertension and ED, there is, still, much to be understood regarding the overlapping pathways of these conditions. Over the last decade, it is becoming widely accepted that the innate immune system contributes to the pathophysiology of vascular-related diseases. The literature consistently shows that targeting these receptors, mainly TLR4, improves vascular and erectile function. However, while it seems that the receptors of innate immunity impact the disease progression, we are only now uncovering their part in hypertension and ED. Such contributions to our understanding shift the way we are approaching these diseases, and ultimately, will open research avenues for the development of new therapeutics, that hopefully, will be more effective in the management of both conditions.
