Vascular Smooth Muscle Emilin-1 Is a Regulator of Arteriolar Myogenic Response and Blood Pressure

Litteri, Gaia; Carnevale, Daniela; D’Urso, Alessandra; Cifelli, Giuseppe; Braghetta, Paola; Damato, Antonio L.; Bizzotto, Dario; Landolfi, Alessandro; Ros, Francesco Da; Sabatelli, Patrizia; Facchinello, Nicola; Maffei, Angelo; Volpin, Dino; Colombatti, Alfonso; Bressan, Giorgio M.; Lembo, Giuseppe

doi:10.1161/atvbaha.112.254664

Cited by 34 publications

(31 citation statements)

References 11 publications

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“…Both vessels represent the prototype of resistance vessels involved in blood pressure homeostasis. 28,38–41 As expected, enhanced vasorelaxation by AAV-LAV-BPIFB4 was associated with potentiation of eNOS phosphorylation (Online Figure XVB) and interestingly with a reduction of both systolic and diastolic blood pressure (Online Figure XVI). In contrast, transduction with AAV-WT-BPIFB4 did not exert molecular and vasorelaxant effects in this model (Online Figure XV).…”

Section: Resultssupporting

confidence: 64%

Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis

Villa

Carrizzo

Spinelli

et al. 2015

Circulation Research

Self Cite

133

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Rationale Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury. Objective Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease. Methods and Results We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R–like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34+ cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle. Conclusions Longevity-associated variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes.

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Section: Resultssupporting

confidence: 64%

Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis

Villa

Carrizzo

Spinelli

et al. 2015

Circulation Research

Self Cite

133

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“…PI3K/Akt signaling promoted voltage-dependent trafficking of Ca 2ϩ channels to the plasma membrane that increased Ca 2ϩ influx via L-type VOCC and thereby was involved in the myogenic response in mouse second-order mesenteric arteries (197,910). Genetic knockdown of Dicer for 5-6 wk to reduce the global role of microRNAs (miRNAs) lowered BP and myogenic tone in mesenteric arteries by reducing PI3K/Akt signaling and L-type VOCC activity (specifically the ␣2␦1 subunit) (101).…”

Section: Renal Autoregulatory Mechanismsmentioning

confidence: 99%

Renal Autoregulation in Health and Disease

Carlström

Wilcox

Arendshorst

2015

Physiological Reviews

380

383

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Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.

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“…It has also been suggested that emilin-1, an elastin microfibril interface-located protein, is important to stabilize molecular interactions between VSMCs and elastic fibers, which maintain arterial morphology and prevent VSMC migration [81]. Emilin-1 also inhibits TGF-β activation, thus maintaining adequate arterial myogenic response and the integrity of arterial wall [82]. …”

Section: Mmp-2 Contributes To Vsmc Migration By Degrading Ecmmentioning

confidence: 99%

Matrix Metalloproteinase 2 as a Potential Mediator of Vascular Smooth Muscle Cell Migration and Chronic Vascular Remodeling in Hypertension

Belo¹,

Guimaraes²,

Castro³

2015

J Vasc Res

113

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For vascular remodeling in hypertension, it is essential that vascular smooth muscle cells (VSMCs) reshape in order to proliferate and migrate. The extracellular matrix (ECM) needs to be degraded to favor VSMC migration. Many proteases, including matrix metalloproteinases (MMPs), contribute to ECM proteolysis and VSMC migration. Bioactive peptides, hemodynamic forces and reactive oxygen-nitrogen species regulate MMP-2 expression and activity. Increased MMP-2 activity contributes to hypertension-induced maladaptive arterial changes and sustained hypertension. New ECM is synthesized to supply VSMCs with bioactive mediators, which stimulate hypertrophy. MMP-2 stimulates the interaction of VSMCs with newly formed ECM, which triggers intracellular signaling via integrins to induce a phenotypic switch and persistent migration. VSMCs switch from a contractile to a synthetic phenotype in order to migrate and contribute to vascular remodeling in hypertension. MMPs also disrupt growth factors bound to ECM, thus contributing to their capacity to regulate VSMC migration. This review sheds light on the proteolytic effects of MMP-2 on ECM and non-ECM substrates in the vasculature and how these effects contribute to VSMC migration in hypertension. The inhibition of MMP activity as a therapeutic target may make it possible to reduce arterial maladaptation caused by hypertension and prevent the resulting fatal cardiovascular events.

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Vascular Smooth Muscle Emilin-1 Is a Regulator of Arteriolar Myogenic Response and Blood Pressure

Cited by 34 publications

References 11 publications

Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis

Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis

Renal Autoregulation in Health and Disease

Matrix Metalloproteinase 2 as a Potential Mediator of Vascular Smooth Muscle Cell Migration and Chronic Vascular Remodeling in Hypertension

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