Luis A. Martinez‐Lemus

University of Missouri

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Jaume Padilla

University of Missouri

Francisco I. Ramirez‐Perez

University of Missouri

Gerald A. Meininger

University of Missouri

Camila Manrique‐Acevedo

University of Missouri

Annayya R. Aroor

University of Missouri

James R. Sowers

University of Missouri

Christopher Foote

University of Missouri

Guanghong Jia

University of Missouri

Michael A. Hill

University of Missouri

Vincent G. DeMarco

University of Missouri

Cooperative Institutions

University of Missouri

215

Harry S. Truman Memorial Veterans' Hospital

University of Missouri Hospital

University of Missouri Health System

Universidade de São Paulo

Cardiovascular Research Center

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Texas A&M University System

Texas A&M University

Tufts Medical Center

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α ₄ β ₁ Integrin Activation of L-Type Calcium Channels in Vascular Smooth Muscle Causes Arteriole Vasoconstriction

Circulation Research (2002)

Kelli R. Waitkus-Edwards Luis A. Martinez‐Lemus Xin Wu Jerome P. Trzeciakowski Michael J. Davis

A pathway for the regulation of vascular tone appears to involve coupling between integrins and extracellular matrix proteins or their fragments and the subsequent modulation of ion movement across the smooth muscle cell membrane. Here, we report that the activation of L-type voltage-activated Ca 2+ channels occurs through a novel interaction of α 4 β 1 integrin with peptides containing the Leu-Asp-Val (LDV) integrin–binding sequence, which is found in the CS-1 region of an alternately spliced fibronectin variant. Experiments were conducted on arterioles isolated from rat skeletal muscle. Arterioles exhibited sustained concentration-dependent vasoconstriction to LDV peptides but not to Leu-Glu-Val (LEV) control peptides. The constriction was associated with increased smooth muscle cell [Ca 2+ ] i , as measured by using fura 2. The response could be inhibited with a function-blocking anti–α 4 integrin antibody. Removal of the endothelium did not alter the vasoconstrictor response. Further experiments demonstrated that the vasoconstriction was abolished by the L-type Ca 2+ channel inhibitor nifedipine and the Src family kinase inhibitor PP2. In studies of isolated smooth muscle cells using whole-cell patch-clamp methods, the L-type current was enhanced by the LDV but not LEV peptide and was blocked by PP2 or antibodies to α 4 integrin. Collectively, these data indicate that activation of α 4 β 1 integrin leads to enhanced influx of Ca 2+ through L-type channels by activating a tyrosine kinase pathway, leading to vasoconstriction. Involvement of integrins in the modulation of vascular tone may be particularly important in vascular responses to mechanical signals, such as pressure and flow, and to tissue injury after damage to the extracellular matrix.

Arteriole

Myogenic contraction

10.1161/hh0402.105899

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Citations (108)

Integrins and Regulation of the Microcirculation: From Arterioles to Molecular Studies using Atomic Force Microscopy

Microcirculation (2005)

Luis A. Martinez‐Lemus Zhe Sun Andreea Trache JEROME P. TRZCIAKOWSKI Gerald A. Meininger

ABSTRACT Integrins are an important class of receptors for extracellular matrix proteins that can mediate both force transmission, by virtue of their connections with the cell matrix and cytoskeleton; and signal transduction, resulting from the assemblages of signaling proteins that associate with focal contacts. Consequently, integrins have been proposed to be the mechanosensor in vascular smooth muscle and endothelial cells and to play a central role in mechanotransduction. In this regard, mechanical force is an important stimulus for many vascular functions, including contractile and relaxation processes, proliferation, migration, attachment, and cell phenotype determination. Collectively, these functions define physiological properties of the vasculature such as control of blood flow, capillary pressure, permeability, and peripheral vascular resistance, and play a role in pathophysiological processes like hypertension, diabetes, and arteriosclerosis. Our knowledge concerning how integrins sense and transduce physical forces into cellular signals and which integrins are involved is incomplete. Compared to other cell surface receptors, integrins have a relatively low affinity for their binding sites on the extracellular matrix and their affinity can be regulated. These characteristics of integrin–ligand interaction may facilitate dynamic processes such as cell migration, cell remodeling, and contractile activation in response to external forces. Important questions remain concerning the nature and origin of integrin‐mediated signaling in the vascular wall.

Mechanotransduction

Vascular permeability

10.1080/10739680590896054

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Citations (53)

Abstract P199: Uric Acid Promotes Vascular Stiffness, Immune Inflammatory Response and Proteinuria in Western Diet Fed Mice

Hypertension (2015)

Annayya R. Aroor Guanghong Jia Vincent G. DeMarco Javad Habibi Zhe Sun

Increased consumption of a diet high in fructose and fat (western diet, WD) is associated with an increase in cardiovascular disease (CVD) and kidney injury. In this regard, excess hepatic production of uric acid generated from excess fructose consumption is emerging as a risk factor for vascular stiffness, which underpins CVD and kidney injury. We hypothesized that a WD would increase uric acid levels and cardiovascular and renal xanthine oxidase (XO) activity and associated increased vascular stiffness and proteinuria. Furthermore, we proposed that inhibition of XO activity would prevent arterial stiffening and reduce proteinuria in a clinically relevant model of WD-induced CVD and renal injury. Four week-old C57BL6/J male mice were fed a WD containing high fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) with or without allopurinol (125mg/L), a potent XO inhibitor for 16 weeks. XO inhibition significantly attenuated WD-induced increases in plasma and urine uric acid levels and aortic XO activity (WD, 0.225 + 0.031 mU/mL WD + allopurinol, 0.097+ 0.026mU/mL, P<0.05), as well as proteinuria (WD, 20.92 + 2.66 mg/ mg creatinine, WD + allopurinol, 13.48 + 1.56 mg/mg creatinine, P<0.05). XO inhibition had no effect on increases in body weight, fat mass, and HOMA-IR promoted by the WD. Blood pressure was not different between any of the groups. Stiffness of aortic endothelial cells, extracellular matrix and vascular smooth muscle cells, as determined by atomic force microscopy, was significantly increased in WD mice and this was prevented by XO inhibition. WD induced a significant macrophage pro-inflammatory response in aorta that was significantly suppressed by XO inhibition. Collectively, these findings support the notion that increased XO activity in the vasculature and kidney and increased hepatic production of uric acid secondary to consumption of a WD promotes vascular stiffness, vascular inflammation and a maladaptive immune response that lead to vascular stiffness and kidney injury.

Allopurinol

Glomerulosclerosis

10.1161/hyp.66.suppl_1.p199

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Arterial Stiffening in Western Diet-Fed Mice Is Associated with Increased Vascular Elastin, Transforming Growth Factor-β, and Plasma Neuraminidase

Frontiers in Physiology (2016)

Christopher Foote Jorge A. Castorena‐Gonzalez Francisco I. Ramirez‐Perez Guanghong Jia Michael A. Hill

Consumption of excess fat and carbohydrate (Western diet, WD) is associated with alterations in the structural characteristics of blood vessels. This vascular remodeling contributes to the development of cardiovascular disease, particularly as it affects conduit and resistance arteries. Vascular remodeling is often associated with changes in the elastin-rich internal elastic lamina (IEL) and the activation of transforming growth factor (TGF)-β. In addition, obesity and type II diabetes have been associated with increased serum neuraminidase, an enzyme known to increase TGF- β cellular output. Therefore, we hypothesized that WD-feeding would induce structural modifications to the IEL of mesenteric resistance arteries in mice, and that these changes would be associated with increased levels of circulating neuraminidase and the up-regulation of elastin and TGF-β in the arterial wall. To test this hypothesis, a WD, high in fat and sugar, was used to induce obesity in mice, and the effect of this diet on the structure of mesenteric resistance arteries was investigated. 4-week old, post-weaning mice were fed either a normal diet (ND) or WD for 16 weeks. Mechanically, arteries from WD-fed mice were stiffer and less distensible, with marginally increased wall stress for a given strain, and a significantly increased Young's modulus of elasticity. Structurally, the wall cross-sectional area and the number of fenestrae found in the internal elastic lamina (IEL) of mesenteric arteries from mice fed a WD were significantly smaller than those of arteries from the ND-fed mice. There was also a significant increase in the volume of elastin, but not collagen in arteries from the WD cohort. Plasma levels of neuraminidase and the amount of TGF- in mesenteric arteries were elevated in mice fed a WD, while ex vivo, cultured vascular smooth muscle cells exposed to neuraminidase secreted greater amounts of tropoelastin and TGF- than those exposed to vehicle. These data suggest that consumption of a diet high in fat and sugar causes stiffening of the vascular wall in resistance arteries through a process that may involve increased neuraminidase and TGF- activity, elevated production of elastin, and a reduction in the size and number of fenestrae in the arterial IEL.

Mesenteric arteries

Internal elastic lamina

Elastic fiber

10.3389/fphys.2016.00285

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Citations (36)

Cell on the move: Remodeling of the vascular wall [abstract]

Matt Boone Luis A. Martinez‐Lemus

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Reduced cofilin activity as a mechanism contributing to endothelial cell stiffening in type 2 diabetes

AJP Heart and Circulatory Physiology (2024)

Gavin Power Olubodun M. Lateef Francisco I. Ramirez‐Perez Yoskaly Lazo‐Fernandez Marc A. Augenreich

An emerging instigator of endothelial dysfunction in type 2 diabetes (T2D) is stiffening of the cell. Previous reports suggest that polymerization of filamentous actin (F-actin) is a potential mediator of endothelial stiffening. Actin polymerization is limited by active cofilin, an F-actin-severing protein that can be oxidized, leading to its inactivation and loss of severing capability. Yet, whether these mechanisms are implicated in endothelial stiffening in T2D remains unknown. Herein, we report that endothelial cells exposed to plasma from male and female subjects with T2D, and the aortic endothelium of diabetic male mice ( db/db), exhibit evidence of increased oxidative stress, F-actin, and stiffness. Furthermore, we show reactive oxygen species, including H 2 O 2 , are increased in the endothelium of mesenteric arteries isolated from db/db male mice, and that exposure of endothelial cells to H 2 O 2 induces F-actin formation. We also demonstrate, in vitro, that cofilin-1 can be oxidized by H 2 O 2 , leading to reduced F-actin severing activity. Finally, we provide evidence that genetic silencing or pharmacological inhibition of LIM kinase 1, an enzyme that phosphorylates and thus inactivates cofilin, reduces F-actin and cell stiffness. In aggregate, this work supports inactivation of cofilin as a potential novel mechanism underlying endothelial stiffening in T2D.

Cofilin

10.1152/ajpheart.00667.2024

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Morphological Analysis of Fenestrae in Arteries

Springer eBooks (2018)

Muhammad Moazzam Jawaid Francisco I. Ramirez‐Perez Antoine Plumerault Flora Quilichini José Alonso Solís-Lemus

Lamina

Internal elastic lamina

10.1007/978-3-319-95450-9_23

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Citations (1)

Overproduction of endothelin-1 impairs glucose tolerance but does not promote visceral adipose tissue inflammation or limit metabolic adaptations to exercise

AJP Endocrinology and Metabolism (2019)

Thomas J. Jurrissen Zachary I. Grunewald Makenzie L. Woodford Nathan C. Winn James R. Ball

Endothelin-1 (ET-1) is a potent vasoconstrictor and proinflammatory peptide that is upregulated in obesity. Herein, we tested the hypothesis that ET-1 signaling promotes visceral adipose tissue (AT) inflammation and disrupts glucose homeostasis. We also tested if reduced ET-1 is a required mechanism by which exercise ameliorates AT inflammation and improves glycemic control in obesity. We found that 1) diet-induced obesity, AT inflammation, and glycemic dysregulation were not accompanied by significantly increased levels of ET-1 in AT or circulation in wild-type mice and that endothelial overexpression of ET-1 and consequently increased ET-1 levels did not cause AT inflammation yet impaired glucose tolerance; 2) reduced AT inflammation and improved glucose tolerance with voluntary wheel running was not associated with decreased levels of ET-1 in AT or circulation in obese mice nor did endothelial overexpression of ET-1 impede such exercise-induced metabolic adaptations; 3) chronic pharmacological blockade of ET-1 receptors did not suppress AT inflammation in obese mice but improved glucose tolerance; and 4) in a cohort of human subjects with a wide range of body mass indexes, ET-1 levels in AT, or circulation were not correlated with markers of inflammation in AT. In aggregate, we conclude that ET-1 signaling is not implicated in the development of visceral AT inflammation but promotes glucose intolerance, thus representing an important therapeutic target for glycemic dysregulation in conditions characterized by hyperendothelinemia. Furthermore, we show that the salutary effects of exercise on AT and systemic metabolic function are not contingent on the suppression of ET-1 signaling.

Proinflammatory cytokine

10.1152/ajpendo.00178.2019

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ADAM17 Cleaves the Insulin Receptor Ectodomain on Endothelial Cells and Induces Vascular Insulin Resistance

The FASEB Journal (2020)

Thaysa Ghiarone Jorge A. Castorena‐Gonzalez Christopher Foote Francisco I. Ramirez‐Perez Andrew A. Wheeler

Despite efforts to reduce the incidence of type 2 diabetes (T2D) and its cardiovascular consequences, T2D‐associated cardiovascular mortality continues to rise in the US and worldwide. The presence of a pro‐inflammatory state and microvascular insulin resistance are hallmarks of T2D that contribute to cardiovascular disease. The former is associated with increased activity of ADAM17, an enzyme that cleaves the ectodomain of multiple transmembrane proteins, while the latter is characterized by decreased insulin‐induced vasodilatory responses. However, the specific mechanisms, including the potential role(s) of ADAM17, underlying vascular insulin resistance in T2D, remain unknown. We hypothesize that in T2D, increased expression and activation of ADAM17 sheds the insulin receptor ectodomain (IRα) from endothelial cells and thus impairs insulin‐induced vasodilation. We tested this hypothesis using isolated small visceral arteries from T2D and non‐T2D subjects undergoing bariatric surgery and cultured human endothelial cells. Results indicate that arteries from subjects with T2D exhibit increased ADAM17 expression, reduced presence of TIMP3 (the endogenous inhibitor of ADAM17), decreased extracellular IRα, and impaired insulin‐induced vasodilation in comparison with arteries from non‐T2D subjects (P<0.05). In vitro , ADAM17 cleaved insulin receptor recombinant proteins at a specific extracellular site of the IRβ subunit (p<0.05). Exposure of endothelial cells to the PKC activator, PMA, increased the shedding activity of ADAM17 (P<0.05) and decreased the presence of IRα on cell surfaces occupied by ADAM17, as observed using super‐resolution microscopy. Moreover, pharmacological inhibition of ADAM17 with TAPI‐0 rescued PMA‐induced impairments in insulin signaling in endothelial cells and insulin‐stimulated vasodilation in human small visceral arteries (P<0.05). Collectively, these findings suggest that ADAM17‐mediated shedding of IR ectodomains from the endothelial surface impairs insulin‐mediated vasodilation. Therefore, inhibition of ADAM17 sheddase activity should be considered a potential new therapeutic strategy to restore vascular insulin sensitivity in T2D. Support or Funding Information Research support: National Institutes of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).

Ectodomain

Insulin receptor substrate

10.1096/fasebj.2020.34.s1.02460

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Mitochondrial functional impairment in response to environmental toxins in the cardiorenal metabolic syndrome

Archives of Toxicology (2015)

Guanghong Jia Annayya R. Aroor Luis A. Martinez‐Lemus James R. Sowers

PINK1

Pathogenesis

10.1007/s00204-014-1431-3

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Citations (39)