Congenic strains reveal the effect of the renin gene on skeletal muscle angiogenesis induced by electrical stimulation

Abstract

de Resende MM, Amaral SL, Moreno C, Greene AS. Congenic strains reveal the effect of the renin gene on skeletal muscle angiogenesis induced by electrical stimulation. Physiol Genomics 33: 33-40, 2008. First published January 15, 2008 doi:10.1152/physiolgenomics.00150.2007.-Previous studies have indicated the importance of angiotensin II (ANG II) in skeletal muscle angiogenesis. The present study explored the effect of regulation of the renin gene on angiogenesis induced by electrical stimulation with the use of physiological, pharmacological, and genetic manipulations of the renin-angiotensin system (RAS). Transfer of the entire chromosome 13, containing the physiologically regulated renin gene, from the normotensive inbred Brown Norway (BN) rat into the background of an inbred substrain of the Dahl salt-sensitive (SS/Mcwi) rat restored renin levels and the angiogenic response after electrical stimulation. This restored response was significantly attenuated when SS-13 BN /Mcwi consomic rats were treated with lisinopril or high-salt diet. The role of ANG II on this effect was confirmed by the complete restoration of skeletal muscle angiogenesis in SS/Mcwi rats infused with subpressor doses of ANG II. Congenic strains derived from the SS-13 BN /Mcwi consomic were used to further verify the role of the renin gene in this response. Microvessel density was markedly increased after stimulation in congenic strains that contained the renin gene from the BN rat (congenic lines A and D). This angiogenic response was suppressed in control strains that carried regions of the BN genome just above (congenic line C) or just below (congenic line B) the renin gene. The present study emphasizes the importance of maintaining normal renin regulation as well as ANG II levels during the angiogenesis process with a combination of physiological, genetic, and pharmacological manipulation of the RAS. renin-angiotensin system; chromosomal substitution THE IMPORTANCE of the renin-angiotensin system (RAS) in controlling sodium homeostasis and vascular resistance is well established; however, in the past decade, much attention has been focused on the importance of angiotensin II (ANG II) as a regulator of microvessel density. Studies from our laboratory (2-4, 15, 37, 42) over the last 5 years have shown that ANG II is an essential component of the control system regulating microvessel density in the skeletal muscle. We have shown that inhibition of RAS activity with the use of pharmacological blockers of ANG II formation and blockade of the angiotensin type 1 (AT 1 ) receptor significantly attenuated the skeletal muscle angiogenic response of normotensive rats induced by exercise (3) and electrical stimulation (2). In addition, we found (37) that chronic infusion of ANG II, at subpressor doses, completely restored the angiogenesis response induced by electrical stimulation in rats fed a high-salt diet. The effects of high salt on microvascular structure and function in the absence of hypertension have been largely attributed to the suppress...

Bone marrow mononuclear cells induce beneficial remodeling and reduce diastolic dysfunction in the left ventricle of hypertensive SS/MCWi rats

“…The SS/MCWi rat has been inbred from the DahlS parent strain at the Medical College of Wisconsin and exhibits both saltsensitive hypertension and microvascular rarefaction (3,5). Recent work has also shown that BMMNC derived from the SS/MCWi rat are not capable of inducing neovascularization in a hindlimb angiogenesis model (6).…”

“…Recent work has also shown that BMMNC derived from the SS/MCWi rat are not capable of inducing neovascularization in a hindlimb angiogenesis model (6). Genetic introgression of chromosome 13 from the nonhypertensive Brown Norway (BN) rat onto the SS/MCWi background (SS-13 BN /MCWi rat) rescues the SS/MCWi rat from salt-sensitive hypertension and vessel rarefaction (5) and also restores the capability of BMMNC to promote skeletal muscle angiogenesis (6). Thus there is a gene or genes located on chromosome 13 important for the therapeutic efficacy of BMMNC for neovascularization in the hindlimb.…”

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).…”

“…In this lowrenin model of hypertension, impaired regulation of the RAS results in reduced microvascular density (44) and an inhibited angiogenic response in skeletal muscle (3,4), both of which can be ameliorated by a subpressor administration of ANG II (16,51). In previous studies we have shown that the angiogenic phenotype in the SS rat can also be restored through introgression of a portion of chromosome (Chr) 13 from Brown Norway BN/NHsdMcwi (BN) that contains the renin gene and is as small as 4.05 Mb (14). Interestingly, sequencing studies have revealed that there are no differences in the coding region or the 5=-flanking proximal promoter region of the renin gene between SS and BN rats.…”

“…Three candidate regions within the already identified 4.05 Mb region (14) on Chr 13 were studied by the development of subcongenics strains; two congenic strains capturing a 0.89 Mb portion and a 2.62 Mb portion of Chr 13, which exclude the BN renin allele, and a third strain, which contains a 2.02 Mb overlapping region including the BN renin allele, were studied. The 4.05 Mb region including all three candidate regions was also sequenced in the SS and BN strains.…”