Recruitment of vascular smooth muscle cells (SMC) by endothelial cells (EC) is essential for angiogenesis. Endothelial-derived heparin binding EGF-like growth factor (HB-EGF) was shown to mediate this process by signaling via ErbB1 and ErbB2 receptors in SMCs. 1) Analysis of ErbB-ligands demonstrated that primary ECs expressed only HB-EGF and neuregulin-1. 2) Primary SMCs expressed ErbB1 and ErbB2, but not ErbB3 or ErbB4. 3) Consistent with their known receptor specificities, recombinant HB-EGF, but not neuregulin-1, stimulated tyrosine phosphorylation of ErbB1 and ErbB2 and migration in SMCs. 4) Neutralization of HB-EGF or inhibition of ErbB1 or ErbB2 blocked 70-90% of the potential of ECs to stimulate SMC migration. Moreover, 5) angiopoietin-1, an EC effector with a role in recruitment of SMC-like cells to vascular structures in vivo, enhanced EC-stimulated SMC migration by a mechanism involving up-regulation of endothelial HB-EGF. Finally, 6) immunohistochemical analysis of developing human tissues demonstrated that HB-EGF was expressed in vivo in ECs associated with SMCs or pericytes but not in ECs of the hyaloid vessels not associated with SMCs. These results suggest an important role for HB-EGF and ErbB receptors in the recruitment of SMCs by ECs and elaborate on the mechanism by which angiopoietins exert their vascular effects.

Decorin is a small extracellular chondroitin/dermatan sulfate proteoglycan that has previously been shown to be involved in the angiogenesis-like behavior of endothelial cells (ECs) in vitro. There is also evidence that decorin plays a role in angiogenesis in vivo. In this study we sought to further explore the involvement of decorin in angiogenesis in vivo, especially in that associated with inflammation. We found by CD31 immunostaining of ECs that in giant cell arteritis there are capillary blood vessels not only in the adventitia as in uninvolved temporal artery wall, but also in the media and the external zone of the thickened intima. Localization of decorin by antiserum LF-30 in adjacent sections showed that in normal temporal artery wall decorin resides mainly in the media and the adventitia, whereas in inflamed temporal artery wall decorin is distributed throughout the vessel wall including the intima. Furthermore, the most intense reaction for decorin was evident in ECs of capillary neovessels within the media and the thickened intima of inflamed temporal artery wall. Decorin was also found in capillary ECs in certain pathological and physiological conditions in which the pivotal role of angiogenesis is more generally accepted. Pyogenic granulomas, granulation tissue of healing dermal wounds, and ovaries at different phases of follicle and corpus luteum formation all contained widely distributed CD31-positive capillaries. Decorin, on the other hand, was found in capillary ECs in pyogenic granulomas and granulation tissue, but not in those in the ovaries. The assessment of the degree of inflammation in the specimens with the presence of CD68-positive macrophages showed that the pyogenic granuloma, granulation tissue, and giant cell arteritis specimens were rich in macrophages around the decorin-positive capillaries. In contrast, the ovarian specimens were populated with fewer macrophages and even they were not located in close vicinity of capillaries negative for decorin. Our results confirm that decorin is involved in angiogenesis in vivo and, particularly, in conditions in which the inflammatory component is dominant.

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All patients with primary hyperparathyroidism should undergo localization studies before reoperation, but it is not known which method is most accurate. The purpose of this prospective study was to compare the performance of planar scintigraphy with 123 I/ 99m Tc-sestamibi, 99m Tc-sestamibi SPECT (SPECT/CT), 11 C-methionine PET/CT, and selective venous sampling (SVS) in persistent primary hyperparathyroidism. Methods: Twenty-one patients referred for reoperation of persistent hyperparathyroidism were included and investigated with 123 I/ 99m Tc-sestamibi, SPECT/CT (n 5 19), 11 C-methionine PET/CT, and SVS (n 5 18) before reoperation. All patients had been operated on 1-2 times previously because of hyperparathyroidism. The results of the localization studies were compared with operative findings, histology, and biochemical cure. Results: Eighteen (86%) of 21 patients were biochemically cured. Nineteen parathyroid glands (9 adenomas, 1 atypical adenoma, and 9 hyperplastic glands) were removed from 17 patients, and 1 patient who was biochemically cured had an unclear histology result. The accuracy for localizing a pathologic parathyroid gland to the correct side of the neck was 59% (95% confidence interval [CI], 36%-79%) for 123 I/ 99m Tc-sestamibi, 19% (95% CI, 5%-42%) for SPECT/CT, 65% (95% CI, 43%-84%) for 11 C-methionine PET/CT, and 40% (95% CI, 19%-65%) for SVS (P , 0.01 for 123 I/ 99m Tc-sestamibi vs. SPECT/ CT). The corresponding accuracy for the correct quadrant or more specific site was 48% (95% CI, 27%-69%) for 123 I/ 99m Tc-sestamibi, 14% (95% CI, 3%-36%) for SPECT/CT, 61% (95% CI, 39%-80%) for 11 C-methionine PET/CT, and 25% (95% CI, 9%-49%) for SVS (P , 0.02 for 123 I/ 99m Tc-sestamibi vs. SPECT/CT). In the 3 patients not cured, preoperative 123 I/ 99m Tc-sestamibi and SPECT/CT remained negative, SVS was false predictive in all, and 11 C-methionine PET/CT in 1. 11 C-methionine PET/CT accurately revealed the pathologic gland in 4 of 8 (50%) patients with a negative 123 I/ 99m Tc-sestamibi scan result, all of whom were biochemically cured after reoperation. Conclusion: Planar scintigraphy with 123 I/ 99m Tc-sestamibi performs well in complicated primary hyperparathyroidism and is recommended as first-line imaging before reoperation. 11 C-methionine PET/CT provides valuable additional information if 123 I/ 99m Tc-sestamibi scan results remain negative. 99m Tc-sestamibi SPECT/CT and SVS provide no additional information, compared with the combined results of 123 I/ 99m Tcsestamibi and 11 C-methionine PET/CT imaging.Key Words: primary hyperparathyroidism; persistent; reoperation; 123 I/ 99m Tc-sestamibi; SPECT-CT; 11 C-methionine PET/CT; selective venous sampling; PTH Nucl Med 2013; 54:739-747 DOI: 10.2967/jnumed.112.109561 Pri mary hyperparathyroidism is a common endocrine disease, with a peak incidence in women aged 50-60 y (1). It is explained by a single parathyroid adenoma in 80%-85% of patients, double adenomas in about 4%, and parathyroid hyperplasia in 15%-20% of cases. Parathyroid carcinoma is...