Korean J Urol.  2013 Nov;54(11):721-731.

Androgens Modulate Endothelial Function and Endothelial Progenitor Cells in Erectile Physiology

• Traish AM
• Galoosian

Abstract

The incidence of erectile dysfunction (ED) increases with age and cardiovascular disease risk factors, such as hypertension, hyperlipidemia, insulin resistance, obesity, and diabetes. These risk factors are thought to contribute to endothelial dysfunction and atherosclerosis, thus contributing to the pathophysiology of ED. The role of the endothelium in regulating erectile physiology is well established. However, the role of androgens in modulating endothelial function and endothelial repair mechanisms subsequent to vascular injury in erectile tissue remains a subject of intensive research. The clinical and preclinical evidence discussed in this review suggests that androgens regulate endothelial function and also play an important role in the development and maturation of endothelial progenitor cells (EPCs), which are thought to play a critical role in repair of endothelial injury in vascular beds. In this review, we discuss the data available on the effects of androgens on endothelial function and EPCs in the repair of vascular injury. Indeed, more research is needed to fully understand the molecular and cellular basis of androgen action in regulating the development, differentiation, maturation, migration, and homing of EPCs to the site of injury. A better understanding of these processes will be critical to the development of new therapeutic approaches to the treatment of vascular ED.

Keyword

Endothelium; Erectile dysfunction; Nitric oxide; Testosterone; Vascular endothelial cells

MeSH Terms

Androgens*
Atherosclerosis
Cardiovascular Diseases
Endothelial Cells
Endothelium
Erectile Dysfunction
Hyperlipidemias
Hypertension
Incidence
Insulin Resistance
Male
Nitric Oxide
Obesity
Risk Factors
Stem Cells*
Testosterone
Vascular System Injuries
Androgens
Nitric Oxide
Testosterone

Figure

• 

  FIG. 1 (A) Potential pathway of bone marrow origin of endothelial progenitor cells and the various triggers and cell surface antigens of the putative endothelial cells. According to current knowledge in the literature, testosterone upregulates vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), metallopeptidase-9 (MMP-9), and other modulators of endothelial progenitor cell (EPC) proliferation. The bone marrow hemangioblast is a common precursor of both hematopoietic stem cells and bone marrow-derived angioblasts. The bone marrow angioblasts further differentiate into endothelial progenitor cells. (B) Differentiation of early and late endothelial progenitor cells and appearance of various cell surface antigens. The exact cell antigens associated with early and late EPCs are not fully understood. In this diagram, we present a schematic of early and late EPCs on the basis of a review of the scientific literature. Both phenotypes exhibit kinase-insert domain receptor (KDR) antigen, whereas CD-133, von Willebrand factor (vWF), and endothelial nitric oxide synthase (eNOS) appear to be markers for a more mature progenitor cell type. c-Kit, proto-oncogene c-Kit; m-KitL, Murine Kit ligand.

• 

  FIG. 2 A proposed role of androgens in regulating endothelial progenitor cell (EPC) proliferation from stromal cells. Testosterone (T) binds to androgen receptors (ARs) on the cell membrane or diffuses into the cell and binds to the intracellular classic AR. The AR ligand complex may exert genomic effects by upregulating vascular endothelium growth factor (VEGF) and mitotic cyclins or by increasing the expression of matrix metallopeptidase-9 (MMP-9) and nitric oxide (NO) in the cytoplasm. T may also have nongenomic effects by directly activating a cascade of signaling resulting in increased NO and VEGF. All of these molecules potentially increase the proliferation of EPCs from the bone marrow. eNOS, endothelial nitric oxide synthase; sGC, soluble guanylyl cyclase; GTP, guanosine triphosphate; GMP, guanosine monophosphate; PDE, phosphodiesterase.

• 

  FIG. 3 Testosterone deficiency is a common link among various causes of endothelial injuries.

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  FIG. 4 Vascular endothelial injury and the pathophysiology of erectile dysfunction. In erectile dysfunction owing to arterial insufficiency, a lower oxygen tension is recorded in corporeal blood, which can lead to veno-occlusive dysfunction. This schematic diagram further suggests the role of the vascular endothelium in erectile physiology and pathophysiology. Adapted from Saenz de Tejada, et al. J Sex Med 2005;2:26-39 [6].

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