Harnessing axonal transport to map reward circuitry: Differing brain-wide projections from medial forebrain domains.

Neurons project long axons that contact other distant neurons. Projections can be mapped by hijacking endogenous membrane trafficking machinery by introducing tracers. To witness functional connections in living animals, we developed a tracer detectible by magnetic resonance imaging (MRI), Mn(II).

Role for PKCβ in enhanced endothelin-1-induced pulmonary vasoconstrictor reactivity following intermittent hypoxia.

Intermittent hypoxia (IH) resulting from sleep apnea causes both systemic and pulmonary hypertension. Enhanced endothelin-1 (ET-1)-induced vasoconstrictor reactivity is thought to play a central role in the systemic hypertensive response to IH. However, whether IH similarly increases pulmonary vasoreactivity and the signaling mechanisms involved are unknown.

Impairment of coronary endothelial cell ET(B) receptor function after short-term inhalation exposure to whole diesel emissions.

Air pollutant levels positively correlate with increases in both acute and chronic cardiovascular disease. The pollutant diesel exhaust (DE) increases endothelin (ET) levels, suggesting that this peptide may contribute to DE-induced cardiovascular disease. We hypothesized that acute exposure to DE also enhances ET-1-mediated coronary artery constrictor sensitivity.

ASIC1 contributes to pulmonary vascular smooth muscle store-operated Ca(2+) entry.

Acid-sensing ion channels (ASIC) are voltage-insensitive, cationic channels that have recently been identified in vascular smooth muscle (VSM). It is possible that ASIC contribute to vascular reactivity via Na(+) and Ca(2+) conductance; however, their function in VSM is largely unknown. In pulmonary VSM, store-operated Ca(2+) entry (SOCE) plays a significant role in vasoregulatory mechanisms such as hypoxic pulmonary vasoconstriction and receptor-mediated arterial constriction.

Reactive oxygen species mediate RhoA/Rho kinase-induced Ca2+ sensitization in pulmonary vascular smooth muscle following chronic hypoxia.

Recent evidence supports a prominent role for Rho kinase (ROK)-mediated pulmonary vasoconstriction in the development and maintenance of chronic hypoxia (CH)-induced pulmonary hypertension. Endothelin (ET)-1 contributes to the pulmonary hypertensive response to CH, and recent studies by our laboratory and others indicate that pulmonary vascular reactivity following CH is largely independent of changes in vascular smooth muscle (VSM) intracellular free calcium concentration ([Ca(2+)](i)). In addition, CH increases generation of reactive oxygen species (ROS) in pulmonary arteries, which may underlie the shift toward ROK-dependent Ca(2+) sensitization.

Reduced store-operated Ca2+ entry in pulmonary endothelial cells from chronically hypoxic rats.

Chronic hypoxia (CH)-induced pulmonary hypertension may influence basal endothelial cell (EC) intracellular Ca(2+) concentration ([Ca(2+)](i)). We hypothesized that CH decreases EC [Ca(2+)](i) associated with membrane depolarization and reduced Ca(2+) entry. To test this hypothesis, we assessed 1) basal endothelial Ca(2+) in pressurized pulmonary arteries and freshly isolated ECs, 2) EC membrane potential (E(m)), 3) store-operated Ca(2+) current (I(SOC)), and 4) store-operated Ca(2+) (SOC) entry in arteries from control and CH rats.

Impaired NO-dependent inhibition of store- and receptor-operated calcium entry in pulmonary vascular smooth muscle after chronic hypoxia.

We have recently demonstrated that chronic hypoxia (CH) attenuates nitric oxide (NO)-mediated decreases in pulmonary vascular smooth muscle (VSM) intracellular free calcium concentration ([Ca2+]i) and promotes NO-dependent VSM Ca2+ desensitization. The objective of the current study was to identify potential mechanisms by which CH interferes with regulation of [Ca2+]i by NO. We hypothesized that CH impairs NO-mediated inhibition of store-operated (capacitative) Ca2+ entry (SOCE) or receptor-operated Ca2+ entry (ROCE) in pulmonary VSM.

Mispolarization of desmosomal proteins and altered intercellular adhesion in autosomal dominant polycystic kidney disease.

Polycystin-1, the product of the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), has been shown to associate with multiple epithelial cell junctions. Our hypothesis is that polycystin-1 is an important protein for the initial establishment of cell-cell junctions and maturation of the cell and that polycystin-1 localization is dependent on the degree of cell polarization. Using laser-scanning confocal microscopy and two models of cell polarization, polycystin-1 and desmosomes were found to colocalize during the initial establishment of cell-cell contact when junctions were forming.

Nitric oxide synthase-inhibition hypertension is associated with altered endothelial cyclooxygenase function.

We reported previously that endothelium-intact superior mesenteric arteries (SMA) from N(omega)-nitro-L-arginine (L-NNA)-treated hypertensive rats (LHR) contract more to norepinephrine (NE) than SMA from control rats. Others have shown that nitric oxide (NO) synthase (NOS) inhibition increases cyclooxygenase (COX) function and expression. We hypothesized that augmented vascular sensitivity to NE in LHR arteries is caused by decreased NOS-induced dilation and increased COX product-induced constriction.

Pulmonary PKG-1 is upregulated following chronic hypoxia.

Recent studies from our laboratory indicate that pulmonary vasodilatory responses to exogenous nitric oxide (NO) are attenuated following chronic hypoxia (CH) and that this NO-dependent vasodilation is mediated by cGMP. Similarly, we have demonstrated that CH attenuates vasodilatory responses to the cGMP analog 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP). We hypothesized that attenuated pulmonary vasodilation to 8-BrcGMP following CH is mediated by decreased protein kinase G-1 (PKG-1) expression/activity.