Essential Role of Bone Marrow for Microvascular Endothelial and Metabolic Functions in Mice

Abstract

Rationale:We have previously demonstrated that the importance of endothelium-derived hyperpolarizing factor (EDHF) increases as the vessel size decreases and that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an EDHF in animals and humans, for which endothelial nitric oxide synthase (eNOS) is the major source. Recent studies have suggested the important role of the bone marrow (BM) in modulating cardiovascular and metabolic functions.Objective: We aimed to examine whether BM plays a role in modulating microvascular endothelial and metabolic functions in mice, and if so, to elucidate the mechanisms involved. Key Words: nitric oxide synthases Ⅲ endothelium-derived hyperpolarizing factor Ⅲ bone marrow Ⅲ adiponectin T he endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilators, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). [1][2][3] It is widely accepted that EDHF plays an important role in modulating vascular tone, especially in microvessels. 4,5 In addition, endothelial function is impaired by hypertension, glucose intolerance, insulin resistance, dyslipidemia, obesity, and metabolic syndrome. 6 -9 Methods and Results: Male eNOS؊ Editorial, see p 12We have previously demonstrated that endotheliumderived hydrogen peroxide (H 2 O 2 ) is an EDHF in mouse 10 and human 11 mesenteric arteries and porcine coronary microvessels. 12 Other investigators confirmed the importance of H 2 O 2 as an EDHF 13 in human 14 and canine 15,16 coronary microvessels and porcine pial arteries. 17 We also have demonstrated that endothelial nitric oxide synthase (eNOS) is a major source of EDHF/H 2 O 2 , 10 where copper, zincsuperoxide dismutase plays an important role to dismutate eNOS-derived superoxide anions to EDHF/H 2 O 2 18,19 and that endothelial NOSs system plays different roles depending on the vessel size, serving as the NO-generating system in large arteries and as the EDHF/H 2 O 2 -generating system in microvessels in mice. 20 Furthermore, we have recently demonstrated that when the all 3 NOSs [eNOS, neuronal NOS (nNOS), and inducible NOS (iNOS)] are genetically deleted in mice, acute myocardial infarction develops spontaneously associated with unique phenotypes that resemble metabolic syndrome in humans, including glucose intolerance, hypertension, dyslipidemia, and visceral obesity. 21 These results indicate the close coupling between microvascular endothelial functions and metabolic disorders, although the detailed mechanisms remain to be elucidated. Original received March 27, 2012; revision received April 20, 2012; accepted April 24, 2012. In March 2012 30 We hypothesized that the BM plays an important role in maintaining microvascular endothelial and metabolic functions. To test this hypothesis, we examined whether BM transplantation improves microvascular endothelial and metabolic functions in eNOS Ϫ/Ϫ mice, an established animal model of atherosclerosis and metabolic disorders, and if so, ...

RhoA/Rho-Kinase in the Cardiovascular System

“…82 Bone marrow and adiponectin derived from adipose tissues also contribute to the modulation of microvascular EDH responses. 83 The role of H 2 O 2 as an EDH factor has led to extensive research on the importance and complexity of endothelium-derived relaxing factors.…”

Disruption of Physiological Balance Between Nitric Oxide and Endothelium-Dependent Hyperpolarization Impairs Cardiovascular Homeostasis in Mice

“…15,16 Thus, EDH rather than NO plays a dominant role in small resistance vessels where blood pressure and organ perfusion are finely regulated. Indeed, accumulating evidence has demonstrated the critical roles of EDH in modulating blood pressure 17 and vascular metabolic functions 18 in general and coronary autoregulation 19 and metabolic dilatation 20 in particular. We have previously demonstrated the diverse roles of the NO synthases (NOSs) system in the endothelium depending on blood vessel size.…”

Role of Endothelial Nitric Oxide Synthase and Collagen Metabolism in Right Ventricular Remodeling due to Pulmonary Hypertension

“…The eNOS -/-mice were originally provided by P. Huang (Harvard Medical School, Boston, MA, USA), 21 which were backcrossed to C57BL/6 mice over 10 generations. Thus, C57BL/6 mice were used as a wildtype (WT) control.…”

“…Thus, C57BL/6 mice were used as a wildtype (WT) control. 21 Col R/R mice and their WT controls were purchased from the Jackson Laboratory (Bar Harbor, MN, USA). 22 The interstitial collagenases of the MMP family initiate degradation of type I collagen by cleavage at a single highly conserved site between Gly 775 and Ile 776 of the α1(1) chain.…”