The roles of the choroid plexus (CP) and cerebrospinal fluid (CSF) production have drawn increasing attention in Alzheimer’s disease (AD) research. Specifically, studies document markedly decreased CSF production and turnover in moderate-to-severe AD. Moreover, reduced CP function and CSF turnover lead to impaired clearance of toxic metabolites, likely promote neuroinflammation, and may facilitate neuronal death during AD progression. We analyzed CP gene expression in AD compared with control subjects, specifically considering those genes involved with CSF production and CP structural integrity. The Brown-Merck Gene Expression Omnibus (GEO) database (CP transcripts) was mined to examine changes in gene expression in AD compared to controls with a focus on assorted genes thought to play a role in CSF production. Specifically, genes coding for ion transporters in CP epithelium (CPE) and associated enzymes like Na–K-ATPase and carbonic anhydrase, aquaporins, mitochondrial transporters/enzymes, blood–cerebrospinal fluid barrier (BCSFB) stability proteins, and pro-inflammatory mediators were selected for investigation. Data were analyzed using t test p-value and fold-change analysis conducted by the GEO2R feature of the GEO database. Significant expression changes for several genes were observed in AD CP. These included disruptions to ion transporters (e.g., the solute carrier gene SLC4A5, p = 0.004) and associated enzyme expressions (e.g., carbonic anhydrase CA4, p = 0.0001), along with decreased expression of genes involved in BCSFB integrity (e.g., claudin CLDN5, p = 0.039) and mitochondrial ATP synthesis (e.g., adenosine triphosphate ATP5L, p = 0.0004). Together all changes point to disrupted solute transport at the blood–CSF interface in AD. Increased expression of pro-inflammatory (e.g., interleukin IL1RL1, p = 0.00001) and potential neurodegenerative genes (e.g., amyloid precursor APBA3, p = 0.002) also implicate disturbed CP function. Because the altered expression of numerous transcripts in AD-CP help explain decreased CSF production in AD, these findings represent a first step towards identifying novel therapeutic targets in AD.

Protein kinases have crucial roles in intracellular signal transduction pathways that affect a wide range of biochemical processes, including apoptosis, metabolism, proliferation, and protein synthesis. Vascular endothelial cells are important regulators of vasomotor tone, tissue/organ perfusion, and inflammation. Since its discovery in the late 1970s, a growing body of literature implicates protein kinase C (PKC) in pathways involving angiogenesis, endothelial permeability, microvascular tone, and endothelial activation. Hence the objective of this review, to characterize the role of PKC in vascular endothelial cells. After discussing the basic principles of PKC structure and function, the focus shifts to abnormal PKC activity driving endothelial dysfunction in three major pathologies whose hallmark is significant vascular disease: diabetes mellitus, hypoxia/ischemia-reperfusion injury, and hypertension. Themes addressed include endothelial cell cycle derangement, endothelial oxidative stress, endothelial activation/inflammation, and impaired endothelial barrier integrity. Achieving a comprehensive understanding of endothelial cell-PKC pathophysiology may lead to development of new therapeutic targets for mitigating morbidity and mortality in these disease states.

Endothelin-1 is a potent regulator of vasomotor tone and promotes endothelium-dependent vasoconstriction of vascular smooth muscle. Dysregulated vasomotor tone is a hallmark of microvascular pathology following cardiac surgery involving cardioplegia and cardiopulmonary bypass (CPB). This review begins with a discussion of the molecular biology of endothelin-1, the structure and function of endothelin receptors, and an overview of endothelin signaling pathways and endogenous regulation. Following this, the focus will turn to an exploration of abnormal endothelin-1 activity during and after CPB across different vascular systems, including coronary, pulmonary, skeletal muscle, peripheral, and mesenteric circulation. Finally, this review concludes with a discussion of drugs targeting endothelin-1 signaling pathways to protect vasomotor tone and microvascular function from ischemia/reperfusion-induced damage, highlighting new therapeutic targets to reduce postoperative morbidity and mortality.

Serotonin (5-hydroxytryptamine, 5-HT) is a vasoactive amine and important regulator of vascular tone. Aberrant serotonergic activity contributes to vascular pathology in multiple cardiovascular disease states, including hypertension, diabetes, metabolic syndrome and chronic myocardial ischemia. Serotonin also plays a vital role in postoperative vascular dysfunction after cardioplegic arrest with cardiopulmonary bypass (CP/CPB). Perioperative microvascular dysfunction following CP/CPB manifests as an increased propensity for vasospasm or vasoplegia, with different effects in different tissue beds (coronary, skeletal muscle, pulmonary and systemic microcirculations). Given the importance of serotonin as a modulator of vasogenic responses, we present a selected narrative survey of the current literature concerning the effects of altered serotonergic activity on vascular dysfunction in the context of CP/CPB and other cardiometabolic diseases. This review begins with a discussion of normal serotonin biology and signaling pathways, then moves into disease-specific discussions covering five major areas of focus: metabolic syndrome, diabetes, hypertension, myocardial ischemia and CP/CPB.