Hypersensitivity to Thromboxane Receptor Mediated Cerebral Vasomotion and CBF Oscillations during Acute NO-Deficiency in Rats

), NO-deficiency is often associated with activation of thromboxane receptors (TP). In the present study we hypothesized that in the absence of NO, overactivation of the TP-receptor mediated cerebrovascular signaling pathway contributes to the development of vasomotion and CBF oscillations. synthesis by ozagrel (10 mg/kg iv.) attenuated it. In isolated MCAs U-46619 in a concentration of 100 nM, which induced weak and stable contraction under physiological conditions, evoked sustained vasomotion in the absence of NO, which effect could be completely reversed by inhibition of Rho-kinase by 10 µM Y-27632.These results suggest that hypersensitivity of the TP-receptor – Rho-kinase signaling pathway contributes to the development of low frequency cerebral vasomotion which may propagate to vasospasm in pathophysiological states associated with NO-deficiency

cGMP-Dependent Protein Kinase I Is Crucial for Angiogenesis and Postnatal Vasculogenesis

Background Endothelium-derived nitric oxide plays an important role for the bone marrow microenvironment. Since several important effects of nitric oxide are mediated by cGMP-dependent pathways, we investigated the role of the cGMP downstream effector cGMP-dependent protein kinase I (cGKI) on postnatal neovascularization. Methodology/Principal Findings In a disc neovascularization model, cGKI -/- mice showed an impaired neovascularization as compared to their wild-type (WT) littermates. Infusion of WT, but not cGKI -/- bone marrow progenitors rescued the impaired ingrowth of new vessels in cGKI-deficient mice. Bone marrow progenitors from cGKI -/- mice showed reduced proliferation and survival rates. In addition, we used cGKI alpha leucine zipper mutant (LZM) mice as model for cGKI deficiency. LZM mice harbor a mutation in the cGKI alpha leucine zipper that prevents interaction with downstream signaling molecules. Consistently, LZM mice exhibited reduced numbers of vasculogenic progenitors and impaired neovascularization following hindlimb ischemia compared to WT mice. Conclusions/Significance Our findings demonstrate that the cGMP-cGKI pathway is critical for postnatal neovascularization and establish a new role for cGKI in vasculogenesis, which is mediated by bone marrow-derived progenitors

Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy

Despite their inherent selectivity, targeted therapies such as tyrosine kinase inhibitors (TKIs) can cause unusual adverse effects. Sunitinib and sorafenib are multitargeted TKIs that have been demonstrated to induce hypothyroidism and thyroid dysfunction. Retrospective studies indicate that sunitinib can induce hypothyroidism in 53-85% of patients, and in prospective studies this complication has been reported in 36-71% of patients. Sorafenib has been reported to be responsible for hypothyroidism in 18% of patients with metastatic renal-cell carcinoma. Furthermore, imatinib and sunitinib seem to increase the requirement of levothyroxine in hypothyroid patients. The management of thyroid dysfunction and possible related symptoms, such as fatigue, represents a challenge to oncologists. We propose a diagnostic and therapeutic algorithm for the management of TKI-related hypothyroidism. Prospective trials are needed to define the incidence of overt and subclinical hypothyroidism and thyroid dysfunction during therapy with sunitinib, sorafenib and potentially other TKIs. The safety and efficacy, and optimal dosing and timing of starting replacement therapy in patients affected by TKI-related hypothyroidism need accurate appraisal and should be evaluated prospectively in appropriately designed trials