Somatostatin receptor subtype expression and function in human vascular tissue

Abstract

In animal models the somatostatin analog angiopeptin inhibits intimal hyperplasia by acting primarily through somatostatin receptor 2 (SSTR-2). However, the results of clinical trials using angiopeptin have been disappointing. In this study we showed that human blood vessels express high levels of SSTR-1 with significantly lower levels of SSTR-2 and -4. Samples of normal veins and arteries, as well as atherosclerotic arteries, expressed predominantly SSTR-1. In addition, the levels of SSTR-1 varied between individuals, indicating that the vascular disease process may have affected SSTR gene expression. Immunocytochemical studies demonstrated that SSTR-1 was present in endothelial but not vascular smooth muscle cells. No evidence of SSTR-3 or -5 expression was detected in normal or diseased blood vessels. Two endothelial cell preparations, ECV304 and human umbilical vein endothelial cells, were investigated and shown to express only SSTR-1 and -4. Exposure of these cells to 10 nM somatostatin or 10 nM SSTR-1-specific agonist resulted in alterations to the actin cytoskeleton, as characterized by a loss of actin stress fibers coupled with an increase in lamellipodia formation at the plasma membrane. These results suggest that the lack of effectiveness of angiopeptin in humans may be due to the differential expression of SSTR-1 by human endothelial cells.

Somatostatin, Acting at Receptor Subtype 1, Inhibits Rho Activity, the Assembly of Actin Stress Fibers, and Cell Migration

“…Treatment of thrombin-stimulated cells with SST attenuated stress fiber formation in CCL39-R1 fibroblasts, but not in wild-type CCL39 or CCL39-R2 fibroblasts. This is consistent with our previous finding that SST decreases the abundance and size of actin stress fibers in HUVECs expressing endogenous SSTR1 (22).…”

“…However, there has been increasing interest in the possibility that SST might also inhibit tumor growth by impairing angiogenesis through the inhibition of endothelial cell migration (44,45). Species and vascular bed differences in the expression of SSTRs has made it difficult to determine the receptor subtype responsible for this effect (22,46,47). In many cell types, including endothelial cells, the ability of thrombin to stimulate cell migration is dependent on Rho activation (37,38,48).…”

“…Consistent with this rationale, the findings from this study indicate that SSTR1 (but not SSTR2) stably expressed in fibroblasts inhibits Rho activation, cytoskeletal reorganization, and cell migration by thrombin. We previously reported that in human umbilical vein endothelial cells (HUVECs), which express endogenous SSTR1, but not SSTR2, SST attenuates stress fiber assembly by serum (22), and we have now determined that this attenuation is associated with a decrease in activated, GTP-bound Rho. Moreover, in contrast to most effects of SSTRs that are abolished by PTX, SSTR1 inhibition of NHE1 (16) and, as we now report, Rho activity is PTX-insensitive.…”

Cortical GABA Interneurons in Neurovascular Coupling: Relays for Subcortical Vasoactive Pathways

“…The following primer pairs were used (receptor: GenBank accession number, primers, and length of PCR product): VPAC1: NM_004624. Curtis et al, 2000) and SSTR-3-5 (as described by Dutour et al, 1998) generating PCR fragments of 375, 628, 654, 1035, and 298 for SSTR-1, SSTR-2, SSTR-3, SSTR-4 and SSTR-5, respectively. PCR was performed with 80 pmol of each primer pair using 1-4 l of cDNA generated from DNase-treated RNAs, 250 M of each dNTPs, 3% of dimethylsulfoxide, 1.5-4.0 mM MgCl 2 , 2.5 U TaqDNA polymerase (Qiagen, Hilden, Germany) in a total volume of 50 l. RNAs from EC, SMC, or AST not treated with RT were included in PCR reactions to control for possible contamination.…”

Localisation of somatostatin and somatostatin receptors in benign and malignant ovarian tumours

“…The demonstration of expression of SRIF receptors on stromal cells within ovarian tumours means that SRIF analogues could potentially alter tumour growth indirectly, by inhibiting stromal cell production of growth factors. SRIF receptors have been described in both normal human blood vessels (Curtis et al, 2000) and veins surrounding human cancers (Reubi et al, 1994(Reubi et al, , 1996. IGF-1 stimulates growth of new blood vessels in experimental systems (Nakao-Hayashi et al, 1992) and potentially SRIF analogues may inhibit tumour growth indirectly by decreasing IGF-1 production.…”