Molecular and cellular dynamics of the developing human neocortex.

The development of the human neocortex is highly dynamic, involving complex cellular trajectories controlled by gene regulation. Here we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and the primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence.

Molecular and cellular dynamics of the developing human neocortex at single-cell resolution.

The development of the human neocortex is a highly dynamic process and involves complex cellular trajectories controlled by cell-type-specific gene regulation. Here, we collected paired single-nucleus chromatin accessibility and transcriptome data from 38 human neocortical samples encompassing both the prefrontal cortex and primary visual cortex. These samples span five main developmental stages, ranging from the first trimester to adolescence.

Is Vitamin D Supplementation an Effective Treatment for Hypertension?

Purpose Of The Review: Results from epidemiological studies suggest that vitamin D (VD) deficiency (VDD) may be a cause of hypertension (HTN). However, the results of randomized clinical trials (RCTs) designed to address the impact of VD supplementation on reducing blood pressure (BP) remain equivocal. To determine whether VD might serve as a beneficial treatment option for a specific subset of hypertensive patients, we performed a stratified analysis of RCT data and addressed problems associated with some methodological issues.

Vitamin D Deficiency Accelerates Coronary Artery Disease Progression in Swine.

Objective: The role of vitamin D deficiency in coronary artery disease (CAD) progression is uncertain. Chronic inflammation in epicardial adipose tissue (EAT) has been implicated in the pathogenesis of CAD. However, the molecular mechanism underlying vitamin D deficiency-enhanced inflammation in the EAT of diseased coronary arteries remains unknown.

FOXO1 Mediates Vitamin D Deficiency-Induced Insulin Resistance in Skeletal Muscle.

Prospective epidemiological studies have consistently shown a relationship between vitamin D deficiency, insulin resistance, and type 2 diabetes mellitus (DM2). This is supported by recent trials showing that vitamin D supplementation in prediabetic or insulin-resistant patients with inadequate vitamin D levels improves insulin sensitivity. However, the molecular mechanisms underlying vitamin D deficiency-induced insulin resistance and DM2 remain unknown.

Vitamin D deficiency and essential hypertension.

Essential hypertension (EH) results when the balance between vasoconstriction and vasodilation is shifted in favor of vasoconstriction. This balance is controlled by the interaction of genetic and epigenetic factors. When there is an unstable balance, vitamin D deficiency as an epigenetic factor triggers a shift to the side of vasoconstriction.

Dysregulation of T cell subsets in the pathogenesis of hypertension.

Essential hypertension (EH) and its complications have had a severe impact on public health. However, the underlying mechanisms of the pathogenesis of EH remain largely unknown. Recent investigations, predominantly in rats and mice, have provided evidence that dysregulation of distinct functions of T lymphocyte subsets is a potentially important mechanism in the pathogenesis of hypertension.

Elimination of vitamin D receptor in vascular endothelial cells alters vascular function.

Vitamin D deficiency has been associated with cardiovascular dysfunction. We evaluated the role of the vitamin D receptor (VDR) in vascular endothelial function, a marker of cardiovascular health, at baseline and in the presence of angiotensin II, using an endothelial-specific knockout of the murine VDR gene. In the absence of endothelial VDR, acetylcholine-induced aortic relaxation was significantly impaired (maximal relaxation, endothelial-specific VDR knockout=58% versus control=73%; P<0.

Vitamin D and the heart.

Vitamin D receptors (VDR) are found in cells throughout the cardiovascular system. A variety of experimental studies indicate that the liganded VDR may play an important role in controlling cardiac hypertrophy and fibrosis, regulating blood pressure, and suppressing the development of atherosclerosis. Some, but not all, observational studies in humans provide support for these experimental findings, raising the possibility that vitamin D or its analogs might prove useful therapeutically in the prevention or treatment of cardiovascular disease.

Liganded vitamin D receptor displays anti-hypertrophic activity in the murine heart.

Vitamin D and its analogs have been suggested to have palliative effects in the cardiovascular system. We have examined the effects of co-administration of the vitamin D receptor agonist, paricalcitol, on the hypertension, cardiac hypertrophy and interstitial fibrosis produced by chronic angiotensin II (AII) infusion. Administration of AII (800ng/kg/min) over a 14-day period resulted in increased blood pressure, myocyte hypertrophy, activation of the hypertrophic fetal gene program (atrial natriuretic peptide, B-type natriuretic peptide and alpha skeletal actin gene expression), increased expression of the pro-hypertrophic modulatory calcineurin inhibitor protein 1 (MCIP 1), and increased fibrosis with augmented procollagen 1 and 3 gene expression.

Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy.

Background: A variety of studies carried out using either human subjects or laboratory animals suggest that vitamin D and its analogues possess important beneficial activity in the cardiovascular system. Using Cre-Lox technology we have selectively deleted the vitamin D receptor (VDR) gene in the cardiac myocyte in an effort to better understand the role of vitamin D in regulating myocyte structure and function.

Methods And Results: Targeted deletion of the exon 4 coding sequence in the VDR gene resulted in an increase in myocyte size and left ventricular weight/body weight versus controls both at baseline and following a 7-day infusion of isoproterenol.

A role for the cell cycle phosphatase Cdc25a in vitamin D-dependent inhibition of adult rat vascular smooth muscle cell proliferation.

We have explored the mechanism(s) underlying 1,25 dihydroxyvitamin D's (1,25(OH)(2)D) suppression of agonist-induced vascular smooth muscle cell (VSMC) proliferation. Quiescent cultured adult rat VSMC were treated with 1,25(OH)(2)D for 48h and endothelin (ET) or angiotensin II (AII) for the final 24h. We show that VSMC responded to 1,25(OH)(2)D or its less hypercalcemic analogue RO 25-6760 with ∼70% inhibition of ET-dependent (3)H-thymidine incorporation.

Vitamin D-dependent suppression of endothelin-induced vascular smooth muscle cell proliferation through inhibition of CDK2 activity.

1,25 dihydroxyvitamin D(3) (1,25 (OH)2 D) and its less hypercalcemic analogues have been shown to inhibit the proliferation of vascular smooth muscle cells (VSMC) in culture. However, the mechanism(s) underlying this suppression is not well understood. Here we have shown that 1,25 (OH)2 D and its analogues (RO-25-6760 and RO-23-7553) inhibit endothelin (ET)-dependent DNA synthesis and cell proliferation in neonatal rat aortic VSMC.

Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents.

In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum- and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity.

Endothelin-stimulated human B-type natriuretic peptide gene expression is mediated by Yin Yang 1 in association with histone deacetylase 2.

Increased B-type natriuretic peptide (BNP) gene expression is regarded as one of the hallmarks of cardiac myocyte hypertrophy. Here we demonstrate that both basal- and endothelin-1-dependent stimulation of human (h) BNP gene transcription requires the presence of an intact Yin Yang 1 (YY1) binding site positioned at -62 bp relative to the transcription start site. Mutation of this site reduced both basal and stimulated hBNP promoter activity.

Expression of the vitamin d receptor is increased in the hypertrophic heart.

The liganded vitamin D receptor (VDR) is thought to play an important role in controlling cardiac function. Specifically, this system has been implicated as playing an antihypertrophic role in the heart. Despite this, studies of VDR in the heart have been limited in number and scope.

A role for p38 mitogen-activated protein kinase and c-myc in endothelin-dependent rat aortic smooth muscle cell proliferation.

We have demonstrated recently that endothelin (ET) stimulates rat aortic smooth muscle cell proliferation through an extracellular signal-regulated kinase (ERK)-dependent mechanism. Approximately 70% of ET-dependent [3H]-thymidine incorporation in these cells signals through this system. In the present study, we show that the residual mitogenic activity requires an intact p38 mitogen-activated protein kinase (p38 MAPK) system and increased c-myc gene expression.

1,25-dihydroxyvitamin D inhibits human ANP gene promoter activity.

1,25-dihydroxyvitamin D, through association with its cognate nuclear receptor, has been shown to have important effects in the cardiovascular and renal systems. We have shown previously that the liganded vitamin D receptor (VDR) inhibits hypertrophy and expression of hypertrophy-sensitive genes (i.e.

1,25 dihydroxyvitamin d amplifies type a natriuretic peptide receptor expression and activity in target cells.

1,25 dihydroxyvitamin D (VD) has been shown to exert a number of beneficial effects on cardiovascular function, including reduction in BP and inhibition of cardiac hypertrophy. In an effort to identify a possible mechanistic link between VD and these salutary effects, the role of VD in controlling the activity and expression of the type A natriuretic peptide receptor (NPR-A), a receptor that signals reductions in BP and suppression of cellular growth in the myocardium and vascular wall, was investigated. VD, as well as the nonhypercalcemic analogue RO-25-6760, increased NPR-A-dependent cyclic guanosine monophosphate production and NPR-A gene expression in cultured rat aortic smooth muscle cells.

Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems.

Our recent studies suggest that 1,25-dihydroxyvitamin D3 functions as an endocrine suppressor of renin biosynthesis. Genetic disruption of the vitamin D receptor (VDR) results in overstimulation of the renin-angiotensin system (RAS), leading to high blood pressure and cardiac hypertrophy. Consistent with the higher heart-to-body weight ratio, the size of left ventricular cardiomyocytes in VDR knockout (KO) mice was markedly increased compared with wild-type (WT) mice.

Transcriptional regulation of type B human natriuretic Peptide receptor gene promoter: dependence on Sp1.

The type B natriuretic peptide receptor (NPR-B) is the cognate receptor for the C-type natriuretic peptide and, as such, is responsible for signaling growth-suppressant activity in vascular smooth muscle cells. Here we report the isolation and characterization of the human (h) NPR-B gene promoter. Using 5' rapid amplification of cDNA ends analysis, we have identified the 5' terminus of the hNPR-B gene transcript approximately 732 base pairs upstream from the presumed translation start site of the protein.

Sgk1 mediates osmotic induction of NPR-A gene in rat inner medullary collecting duct cells.

We have shown previously that increased extracellular osmolality stimulates expression and promoter activity of the type A natriuretic peptide receptor (NPR-A) gene in rat inner medullary collecting duct (IMCD) cells through a mechanism that involves activation of p38 mitogen-activated protein kinase (MAPK). The serum and glucocorticoid inducible kinase (Sgk) is thought to participate in the regulation of sodium handling in distal tubular segments. We sought to determine whether this kinase might be involved in the osmotic stimulation of NPR-A gene promoter activity.

Suppression of WEE1 and stimulation of CDC25A correlates with endothelin-dependent proliferation of rat aortic smooth muscle cells.

Proliferation of vascular smooth muscle cells plays a key role in the pathogenesis of several disorders of the vascular wall. Endothelin (ET), a vasoactive peptide that signals through a G protein-coupled receptor, has been linked to mitogenesis in vascular smooth muscle cells, but the mechanistic details underlying this activity remain incompletely understood. In the present study, we demonstrate that ET-dependent mitogenesis in rat neonatal and adult aortic smooth muscle (RASM) cells is accompanied by an increase (up to 10-fold) in CDK2 activity, but not CDK2 protein levels.