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The C-type lectin-like receptor 2 (CLEC-2) is expressed on platelets and mediates binding to podoplanin (PDPN) on various cell types. The binding to circulating tumor cells (CTCs) leads to platelet activation and promotes metastatic spread. An increased level of soluble CLEC-2 (sCLEC-2), presumably released from activated platelets, was shown in patients with thromboinflammatory and malignant disease. However, the functional role of sCLEC-2 and the mechanism of sCLEC-2 release are not known. In this study, we focused on the effect of platelet activation on CLEC-2 expression and the sCLEC-2 plasma level in patients with cancer. First, citrated blood from healthy volunteer donors ( n = 20) was used to measure the effect of platelet stimulation by classical agonists and PDPN on aggregation, CLEC-2 expression on platelets with flow cytometry, sCLEC-2 release to the plasma with ELISA and total CLEC-2 expression with Western blot analysis. Second, sCLEC-2 was determined in plasma samples from healthy donors (285) and patients with colorectal carcinoma (CRC; 194), melanoma (160), breast cancer (BC; 99) or glioblastoma (49). PDPN caused a significant increase in the aggregation response induced by classical agonists. ADP or PDPN stimulation of platelets caused a significant decrease in CLEC-2 on platelets and sCLEC-2 in the plasma, whereas total CLEC-2 in platelet lysates remained the same. Thus, the increased plasma level of sCLEC-2 is not a suitable biomarker of platelet activation. In patients with CRC (median 0.9 ng/mL), melanoma (0.9 ng/mL) or BC (0.7 ng/mL), we found significantly lower sCLEC-2 levels ( p < 0.0001), whereas patients with glioblastoma displayed higher levels (2.6 ng/mL; p = 0.0233) compared to healthy controls (2.1 ng/mL). The low sCLEC-2 plasma level observed in most of the tumor entities of our study presumably results from the internalization of sCLEC-2 by activated platelets or binding of sCLEC-2 to CTCs.

Hypertension and arterial stiffness are significant factors contributing to cardiovascular disease. L-citrulline, a nitric oxide precursor, has been proposed as a nutritional, non-pharmacological blood pressure-lowering intervention. This study aimed to investigate the impact of L-citrulline on central and peripheral blood pressure, pulse wave reflection, and central arterial stiffness at rest and during an isometric knee extension exercise protocol. Twelve older males received 6 g of L-citrulline or a placebo for six days using a double-blind crossover design. Blood hemodynamics parameters (i.e., aortic and brachial systolic and diastolic blood pressure, mean arterial pressure, pulse pressure, heart rate), pulse wave reflection (i.e., augmented pressure, augmentation index, forward/backward wave pressure), and arterial stiffness (i.e., carotid-femoral pulse wave velocity) were measured at baseline, post-supplementation, and during isometric exercise. No significant effects of L-citrulline supplementation were observed at rest or during exercise on blood pressure, pulse wave reflection, or arterial stiffness. Both central and peripheral blood pressure were increased during the exercise, which is consistent with isometric contractions. The results of the present study do not support any blood pressure-lowering effect of short-term L-citrulline at rest or during low-intensity isometric exercise compared to the pre-exercise values in older males.