Vascular homing peptides with cell-penetrating properties.

In vivo screening of phage-displayed peptide libraries has revealed extensive molecular heterogeneity in the blood vessels of individual normal tissues and shown that pathological lesions put their signature on the vasculature. In tumors, both blood and lymphatic vessels differ from normal vessels. Moreover, the molecular changes in the vasculature parallel progression in tumor development, hence making the vessels in premalignant lesions distinguishable from normal vessels and from the vessels in malignant tumors of the same tissue. Some of the tumor-homing peptides penetrate into tumor endothelial cells (and tumor cells), but not into endothelial cells in normal tissues or other normal cells. Thus, these cell-penetrating peptides are cell type-specific. Peptides that home to tumor vasculature have been shown to be useful in directing therapeutic agents to experimental tumors. The cell penetrating peptides may be particularly useful in drug delivery because they can take their payload inside the target cells and even into a specific subcellular organelle such as the nucleus.

Arteriolar dilations induced by contraction of hamster cremaster muscle are dependent on changes in endothelial cell calcium.

UNLABELLED: Muscle contraction initiates microvascular arteriolar dilation in regions directly overlapping the active fibres but the cells (vascular smooth muscle cells, endothelial cells) responsible for producing the dilation and the underlying signalling mechanisms are unknown. AIMS: We tested the hypothesis that changes in endothelial cell calcium (Ca2+) are involved in this dilation. METHODS: Four to five muscle fibres lying approximately perpendicular to arterioles (maximum diameter approximately 40 microm) were stimulated (4 Hz, 4-20 V, 0.4 ms duration) and observations were made at the site of muscle fibre/arteriole overlap. RESULTS: Chelation of endothelial cell Ca2+ (with BAPTA) abolished dilations to 120 s of muscle contraction (5.6 +/- 1.5 microm in controls vs. 0.51 +/- 1.2 microm with BAPTA, n = 6), indicating that changes in endothelial cell Ca2+ are required for the response. To determine the time frame of the Ca2+ signal, we monitored whole endothelial cell Ca2+ (with Fura-PE3) prior to and following either 120 (n = 13), 30 (n = 9) or 10 (n = 9) s of muscle contraction. In all instances, no changes in Ca2+ were observed despite typical dilator responses. CONCLUSIONS: These data indicate that (i) the initiation of muscle contraction-induced arteriolar dilations depends on a change in endothelial cell Ca2+, which must be a transient event that takes place early/during stimulation, and (ii) maintenance of the dilation after contraction occurs via mechanisms that are independent of changes in global Ca2+ within the cell.