Therapeutic Angiogenesis for Erectile Dysfunction

Project: Research project

Project Details

Description

Research over the past 25 years has led to the understanding that erectile function is an integrated vascular
process that is dependent on interactions between the vascular endothelium, nerves and cavernosal smooth
muscle;with nitric oxide (NO) the principal mediator of this process. Erectile dysfunction (ED) is a major health
care problem that afflicts some 30 million men in the US and this number is expected to double within the
decade. Hypercholesterolemia is one of the strongest risk factors for the development of ED. Therefore, in
most men with ED, the underlying pathophysiology is a non-traumatic, injury to the vascular bed that impairs
endothelial and vascular smooth muscle cell function within penile tissue. Phosphodiesterase (PDE) 5
inhibitors provide treatment options for patients with ED but do not reverse the vascular injury.
Angiogenesis is the growth and proliferation of endothelial cells from existing vascular structures and
several angiogenic growth factors, including vascular endothelial growth factor (VEGF) and basic fibroblast
growth factor (bFGF), are present in corporal tissue. The central hypothesis in the initial funding period for
DK62997 was that angiogenic growth factors could induce structural and functional benefits in rabbit corporal
tissue in the setting of diet-induced hypercholesterolemia. Though an number of major findings were made
and reported work performed during this same period has also showed that the effects of VEGF and bFGF
were highly dose and route dependent, and local and/or systemic toxicity could readily occur with these
agents. Following injury or angiogenic therapy, a directional association between changes in VEGF ligand and
VEGF receptor signaling in corporal tissue was found;but association is not causality. Targeting individual
cells types within the complex corporal vascular structure is now feasible. In this revised application, we will
test the central hypothesis that a loss of VEGF receptor-ligand signaling within the corpus cavernosum is both
the mechanism for hypercholesterolemia induced ED as well as a target for therapeutic strategies designed to
prevent and reverse ED. To that end, the specific aims are:
I: Establish that a loss of VEGF ligand-mediated receptor signaling within the corpus cavernosum is sufficient
to recapitulate the vascular abnormalities that are caused by hypercholesterolemia induced ED.
II: Establish whether modulation of VEGF signaling, within corporal endothelial cells, is sufficient to
prevent/limit the induction hypercholesterolemia induced vascular injury.
III: When a major end-product of the VEGFR/PI3-kinase-Akt pathway is absent, determine the potential mechanisms of, as well the vulnerability to, hypercholesterolemia induced vascular injury in corporal tissue.
IV: Establish that in the setting of established hypercholesterolemia induced vascular injury modulation of the VEGF receptor-ligand family within endothelium is able to reverse abnormalities in vascular smooth muscle and erectile dysfunction.



Research over the past 25 years has led to the understanding that erectile function is a
complex and integrated vascular process that is dependent on interactions between
many different cells and nitric oxide (NO) the principal mediator of this process. Erectile
dysfunction (ED) is a major health care that afflicts millions of men in the United States.
In a very large number of patients with ED, the underlying problem is a non-traumatic
vascular injury that impairs the endothelial and vascular smooth muscle cell interactions
in penile tissue. This project was funded 4 years ago to test the central hypothesis that
angiogenic growth factors could induce structural and functional benefits in rabbit
corporal tissue in the setting of diet-induced hypercholesterolemia. A number of findings
were made and published. In this renewal, we propose to identify the mechanism for
hypercholesterolemia induced vascular injury as well as how to employ information
gained in the studies to advance potential treatments for ED.
StatusNot started

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