Smooth muscle overexpression of IGF-I induces a novel adaptive response to small bowel resection

Abstract

Prior studies of intestinal adaptation after massive small bowel resection (SBR) have focused on growth factors and their effects on amplification of the gut mucosa. Because adaptive changes have also been described in intestinal smooth muscle, we sought to determine the effect of targeted smooth muscle growth factor overexpression on resection-induced intestinal adaptation. Male transgenic mice with smooth muscle cell overexpression of insulin-like growth factor I (IGF-I) by virtue of an alpha-smooth muscle actin promoter were obtained. SMP8 IGF-I transgenic (IGF-I TG) and nontransgenic (NT) littermates underwent 50% proximal SBR or sham operation and were then killed after 3 or 28 days. NT mice showed the expected alterations in mucosal adaptive parameters after SBR, such as increased wet weight and villus height. The IGF-I TG mice had inherently taller villi, which did not increase significantly after SBR. In addition, IGF-I TG mice had a 50% postresection persistent increase in remnant intestinal length, which was associated with an early decline and later increase in relative mucosal surface area. These results indicate that growth factor overexpression within the muscularis layer of the bowel wall induces significant postresection adaptive intestinal lengthening and a unique mucosal response. IGF-I signaling within the muscle wall may play an important role in the pathogenesis of resection-induced adaptation.

Gene transfer with a vector expressing Maxi-K from a smooth muscle-specific promoter restores erectile function in the aging rat

“…Second, consistent with the in vitro data, the ability pSMAA-hSlo transfection to restore erectile function in the aging rat model of ED in vivo is similar to that observed with pVAX-hSlo under most conditions, and statistically better under some conditions (see Figures 2-4; Table 2). Thus, with respect to ED, despite the more limited smooth muscle expression profile, the CN-stimulated ICP response for pSMAA-hSlo compares quite favorably to that observed with hSlo expression driven by the heterologously expressed CMV promoter (the vector used in the recently completed Phase I human clinical trial), [17][18][19][20] as well as our prior preclinical observations with pcDNA/hSlo. [14][15][16] Again, it is important to keep in mind that gene transfer with both promoters produces an ICP/BP ratio commensurate with an erection; that is, an ICP/BP ratio of more than 0.6.…”

“…The mouse SMAA promoter directed tissuespecific expression in all mammalian species thus far studied. [19][20][21][22][23][24][25][26] The purpose of this study was to evaluate the ability of this new construct to restore erectile function in an aging rat model of erectile dysfunction and to compare the results so obtained with that of our current construct, pVAX-hSlo. If the duration of action and efficacy are similar to preclinical studies with pVAXhSlo and pcDNA-hSlo, then the use of pSMAA-hSlo may confer additional therapeutic and regulatory advantages, namely, enhancement of the safety profile of Slo gene transfer by limiting its action to smooth muscle cells only.…”

Exogenous GLP-2 and IGF-I induce a differential intestinal response in IGF binding protein-3 and -5 double knockout mice

“…Consistent with greater bioavailability or expression of IGF-I in mesenchymal cells (20,40), IGFBP-3/-5 KO mice showed a significantly longer small intestine than WT mice. However, unlike mucosa, further growth of muscularis in KO mice was not observed with either GLP-2 or IGF-I treatment.…”

“…This may reflect a need for IGFBP-5 to stimulate further growth of muscularis in response to GLP-2 since overexpression of IGF-I in mesenchyme induces muscularis growth throughout the bowel in association with increased expression of IGFBP-5 in muscularis (40). In our rat model of short bowel syndrome we have noted that GLP-2 increases small intestine length (21), an important goal of rehabilitation therapy in patients with intestinal failure (20). Thus, given the therapeutic potential of GLP-2 to improve intestinal adaptation (13,19), further studies are needed to investigate the role of IGFBP-3/-5 in the growth of muscularis and subsequent lengthing of the bowel in response to GLP-2.…”

Ret heterozygous mice have enhanced intestinal adaptation after massive small bowel resection

“…Adaptation is characterized by increased villus height and crypt depth as a consequence of mitogenic stimuli to intestinal crypt cells via incompletely understood mechanisms. Previous studies demonstrated important roles for many growth factors (9,29,33) and their receptors (44), as well as for smooth muscle (22,27) and angiogenesis (28,33,35) in controlling epithelial proliferation and apoptosis. Enteric nervous system (ENS) function in intestinal adaptation has not been studied in detail.…”