Role of endothelial cell apoptosis in regulation of skeletal muscle angiogenesis during high and low salt intake

Abstract

. Role of endothelial cell apoptosis in regulation of skeletal muscle angiogenesis during high and low salt intake. Physiol Genomics 25: 325-335, 2006. First published February 7, 2006 doi:10.1152/physiolgenomics.00253.2005.-Angiogenesis, under normal conditions, is a tightly regulated balance between pro-and antiangiogenic factors. The goal of this study was to investigate the mechanisms involved in the control of the skeletal muscle angiogenic response induced by electrical stimulation during the suppression of plasma renin activity (PRA) with a high-salt diet. Rats fed 0.4% or 4% salt diets were exposed to electrical stimulation for 7 days. The tibialis anterior (TA) muscles from stimulated and unstimulated hindlimbs were removed and prepared for gene expression analysis, CD31-terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) double-staining assay, and Bcl-2 and Bax protein expression by Western blot. Rats fed a low-salt diet showed a dramatic angiogenesis response in the stimulated limb compared with the unstimulated limb. This angiogenesis response was significantly attenuated when rats were placed on a high-salt diet. Microarray analysis showed that in the stimulated limb of rats fed a low-salt diet many genes related to angiogenesis were upregulated. In contrast, in rats fed a high-salt diet most of the genes upregulated in the stimulated limb function in apoptosis and cell cycle arrest. Endothelial cell apoptosis, as analyzed by CD31-TUNEL staining, increased by fourfold in the stimulated limb compared with the unstimulated limb. There was also a 48% decrease in the Bcl-2-to-Bax ratio in stimulated compared with unstimulated limbs of rats fed a high-salt diet, confirming severe apoptosis. This study suggests that the increase in endothelial cell apoptosis in TA muscle might contribute to the attenuation of angiogenesis response observed in rats fed a high-salt diet.Bax; Bcl-2; gene expression THE GROWTH OF NEW BLOOD VESSELS plays a critical role in normal physiological processes but is also central to the progression of many diseases. Angiogenesis is involved in several disorders such as cancer, diabetic retinopathy, macular degeneration, and endometriosis (15). In an attempt to control pathological angiogenesis, a growing interest in better understanding prosurvival and prodeath signals has emerged (7,8,26,34). Each endothelial cell within a vessel wall is exposed to a combination of prosurvival and prodeath signals. The sum of these signals determines whether the cell remains viable or undergoes apoptosis (10).Our laboratory has demonstrated that physiological, pharmacological, or genetic manipulation of the renin-angiotensin system (RAS) has an important impact on both the basal number of microcirculatory blood vessels and the ability of tissues to undergo angiogenesis induced by exercise (3) or electrical stimulation (2). In previous studies (4), we demonstrated that transfer of a region of chromosome 13 containing the renin gene from Dahl R into Dahl S rats restores both p...

O treinamento físico aeróbio inibe a sinalização apoptótica muscular esquelética mediada por VEGF-VEGR2 em ratos espontaneamente hipertensos

“…It is known that capillary rarefaction occurs in parallel to activation of the apoptotic way which negatively reflects on the angiogenesis and endothelial cellular survival in the skeletal muscle 9 . The Bcl-2/Bcl-x and Bad proteins are important apoptotic regulators which act inhibiting or promoting apoptosis, respectively 10,27 .…”

“…Recent studies have demonstrated that the mechanisms involved in the inhibition of the angiogenic process are associated with increase in the expression of many genes related to apoptosis, considering significant increase in the death of endothelial cells in the skeletal muscle 9 . The authors investigated key-regulatory ways which control the molecular response for apoptosis, especially the Bcl-2 family.…”

“…Many factors have been pointed as responsible for the endothelial dysfunction and by fail in the angiogenic process in hypertension. Among these, we can highlight the crucial role of the nitric oxide (NO) 7 and the vascular endothelial growth factor (VEGF) 8 , as well as the balance of apoptosis stimulators and inhibitors mainly mediated by the B2 cells lymphoma family (Bcl-2) 9 . VEGF is known as a key-regulating protein of the physiological angiogenesis both in the embryogenic and post-natal phases.…”

“…Increase in blood flow to the skeletal musculature promoted by aerobic ET and consequent increase of shear stress present direct correlation with increase in release of NO and VEGF, which also contributes to flow increase, since it leads not only to endothelium--dependent vasodilatation but also to angiogenesis, being considered by many researchers the primary sign for vascular remodeling 20 . At physiological conditions, maintenance, formation and/or loss of capillaries are dependent on a thin balance between positive and negative regulators of angiogenesis 9 . Mediators of cellular signaling have been identified as determinant in the recovery of the microvascular chain in hypertension; however, studies with non-pharmacological approach such as ET, concerning regulation of the angiogenic factors and muscular anti and pro-apoptotic proteins have not been studied.…”

Characterization of the genomic structure and function of regions influencing renin and angiogenesis in the SS rat

“…The RAS has long been known to be an essential modulator of sodium homeostasis and vascular resistance. Recently increasing evidence has implicated this system in the control of microvascular density since inhibition of the RAS pharmacologically (3,4,19,27,44), genetically (5,14), and by high-salt diet (15,16,50,51) inhibits angiogenesis. Others have described local tissue RAS in a variety of organs that act both independently and in concert with the circulating system (22,35,43,47).…”