Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity.
Johnson Kirby D,Hsu Amy P,Ryu Myung-Jeom,Wang Jinyong,Gao Xin,Boyer Meghan E,Liu Yangang,Lee Youngsook,Calvo Katherine R,Keles Sunduz,Zhang Jing,Holland Steven M,Bresnick Emery H
The Journal of clinical investigation
Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2 cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.
Emerging Roles of Vascular Endothelium in Metabolic Homeostasis.
Pi Xinchun,Xie Liang,Patterson Cam
Our understanding of the role of the vascular endothelium has evolved over the past 2 decades, with the recognition that it is a dynamically regulated organ and that it plays a nodal role in a variety of physiological and pathological processes. Endothelial cells (ECs) are not only a barrier between the circulation and peripheral tissues, but also actively regulate vascular tone, blood flow, and platelet function. Dysregulation of ECs contributes to pathological conditions such as vascular inflammation, atherosclerosis, hypertension, cardiomyopathy, retinopathy, neuropathy, and cancer. The close anatomic relationship between vascular endothelium and highly vascularized metabolic organs/tissues suggests that the crosstalk between ECs and these organs is vital for both vascular and metabolic homeostasis. Numerous reports support that hyperlipidemia, hyperglycemia, and other metabolic stresses result in endothelial dysfunction and vascular complications. However, how ECs may regulate metabolic homeostasis remains poorly understood. Emerging data suggest that the vascular endothelium plays an unexpected role in the regulation of metabolic homeostasis and that endothelial dysregulation directly contributes to the development of metabolic disorders. Here, we review recent studies about the pivotal role of ECs in glucose and lipid homeostasis. In particular, we introduce the concept that the endothelium adjusts its barrier function to control the transendothelial transport of fatty acids, lipoproteins, LPLs (lipoprotein lipases), glucose, and insulin. In addition, we summarize reports that ECs communicate with metabolic cells through EC-secreted factors and we discuss how endothelial dysregulation contributes directly to the development of obesity, insulin resistance, dyslipidemia, diabetes mellitus, cognitive defects, and fatty liver disease.
Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension.
Bosch Jaume,Abraldes Juan G,Fernández Mercedes,García-Pagán Juan Carlos
Journal of hepatology
Portal hypertension is the main cause of complications in patients with chronic liver disease. Over the past 25 years, progress in the understanding of the pathophysiology of portal hypertension was followed by the introduction of an effective pharmacological therapy, consisting mainly of treatments aimed at correcting the increased splanchnic blood flow. It is only recently that this paradigm has been changed. Progress in our knowledge of the mechanisms of increased resistance to portal blood flow, of the formation of portal-systemic collaterals, and of mechanisms other than vasodilatation maintaining the increased splanchnic blood flow have opened entirely new perspectives for developing more effective treatment strategies. This is the aim of the current review, which focuses on: (a) the modulation of hepatic vascular resistance by correcting the increased hepatic vascular tone due to hepatic endothelial dysfunction, and (b) correcting the abnormal angiogenesis associated with portal hypertension, which contributes to liver inflammation and fibrogenesis, to the hyperkinetic splanchnic circulation, and to the formation of portal-systemic collaterals and varices.