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Author(s): Lawrence O. Gostin 1,*, Oyewale Tomori 2, Suwit Wibulpolprasert 3, Ashish K. Jha 4, Julio Frenk 5, Suerie Moon 6, Joy Phumaphi 7, Peter Piot 8, Barbara Stocking 9, [...]

An oligonucleotide decoy for transcription factor E2F can be introduced into cultured mesangial cells (MC) by using cationic liposomes. This results in the suppression of cell cycle regulatory genes which stops the proliferation of serum-induced MC. The growth of glomerular MC is a common characteristic of human glomerulonephritis. The decoy is a synthetic double-stranded oligodeoxynucleotide which binds strongly with E2F. It has been used previously to inhibit vascular smooth muscle cell proliferation in vitro and in vivo.

Vascular disease is the most common cause of death in the industrialized world. Although significant progress has been made in treating these disorders, more therapeutic agents must be developed that effectively prevent, arrest, or reverse this disease. Recent insights into the pathogenesis of vascular disease have opened up a new frontier of molecular therapies that target molecules as diverse as adhesion molecules and transcription factors. The biological rationale for these new therapies and their prospects for success are discussed., Insights into the pathogenesis of vascular disease must be based on an understanding of the regulatory processes that maintain the structure and homeostatic functions of the healthy vessel. The vessel [...]

The blood pressure regulator angiotensin binds to two receptors, including the type-2 G-protein-coupled receptor (AT2). This receptor participates in the central nervous system and cardiovascular activities which are regulated by the renin-angiotensin system. In mice devoid of the gene encoding the AT2 receptor, an abnormal drinking response to water deficiency and a rise in vasopressin response to injection of angiotensin II are observed. The embryonic growth and baseline blood pressure are uninfluenced.

A study of the factors influencing vascular smooth muscle cell accumulation indicate that endothelial cell nitric oxide synthase (ec-NOS) is an endogenous inhibitor of in vivo formation of vascular lesions. A Sendai virus/liposome in vivo gene transfer technique enables total expression of ec-NOS in vessel walls. The vascular reactivity of the damaged vessel and NO synthesis increases with ec-NOS gene transfection.

Aging-induced vasculopathy leads to thickening of vessel walls and restructuring of extracellular and cellular matrix components, resulting in atherosclerosis and hypertension. Excessive deposition of smooth muscle cells, mononuclear cells and collagen occurs. Vasculopathy suppresses the development of endothelium derived relaxing factor that mediates the functions of vascular tissues. Elastin, medial collagen muscle and advanced glycosylation end product levels reduce with age-induced vasculopathy.

Conditions contributing to the process of vascular remodeling are reviewed. Vascular remodeling is an adaptive process that alters the structure of the vascular system at the cellular level and occurs in response to long-term hemodynamic conditions. It may lead to the development of vascular diseases and circulatory disorders. The endothelium is the vascular cell most likely to contribute to remodeling by releasing or activating substances that influence the growth, death, or migration of cells, or the composition of the extracellular matrix. Therapeutic interventions in the vascular remodeling process may lead to the treatment of vascular diseases such as atherosclerosis, pulmonary and systemic hypertension, and narrowing of the vasculature (stenosis).

The persistent inactivation of neointimal hyperplasia is attributed to a single intraluminal transport of antisense cdc2 kinase and proliferating-cell nuclear antigen (PCNA) oligonucleotide. The evidence for this specific inhibitory effect of the antisense ODN is gathered by observing the inactivation of vascular smooth muscle cell (VSMC) proliferation, affected by the antisense ODN combination. Sense and missense control ODN do not exhibit control over VSMC proliferation. The inhibition of neointima generation is confined to the region treated with antisense ODN, and its effect is dose-dependent.