Maria Bonaria Salis

University of Sassari

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Costanza Emanueli

Imperial College London

Paolo Madeddu

University of Bristol

Paolo Madeddu

University of Sassari

Tiziana Stacca

University of Sassari

Anna Franca Milia

Associazione Istituzione Libera Università Nuorese

Leonardo Gaspa

University of Sassari

Julie Chao

Medical University of South Carolina

Stefania Straino

Explora (Italy)

Maurizio C. Capogrossi

Johns Hopkins Medicine

Alessandra Minasi

Sapienza University of Rome

Cooperative Institutions

University of Sassari

Istituto Dermopatico dell'Immacolata

Medical University of South Carolina

Istituti di Ricovero e Cura a Carattere Scientifico

Istituto Nazionale Biostrutture e Biosistemi

University of Ferrara

University of Parma

University Hospitals Parma Medical Center

St. Elizabeth's Medical Center

University of Bristol

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Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia

Circulation Research (2002)

Anna Franca Milia Maria Bonaria Salis Tiziana Stacca Alessandra Pinna Paolo Madeddu

Proteinase-activated receptors (PAR-2) are expressed by the cardiovascular system and mediate vasodilation, plasma protein extravasation, and endothelial cell proliferation, all regarded as essential steps for neovascularization. We investigated the angiogenic action of PAR-2 signaling in vivo. The effect of the PAR-2 activating peptide (PAR-2AP, SLIGRL-NH 2 ) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.5 nmol IM daily for 21 days, respectively) was also tested in mice subjected to unilateral limb ischemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR2-AP nor the PAR-2 reverse peptide (PAR-2RP, LRGILS-NH 2 ) did produce any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated hemodynamic recovery and enhanced limb salvage. In conclusions, our study is the first to demonstrate the angiogenic potential of PAR-2 stimulation in vivo. If similar effects occur in humans, PAR-2AP agonists could have some therapeutic potential for the treatment of tissue ischemia.

Therapeutic angiogenesis

Extravasation

Hindlimb

10.1161/01.res.0000031958.92781.9e

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Prevention of Diabetes-Induced Microangiopathy by Human Tissue Kallikrein Gene Transfer

Circulation (2002)

Costanza Emanueli Maria Bonaria Salis Alessandra Pinna Tiziana Stacca Anna Franca Milia

Background— Microvascular insufficiency represents a major cause of end-organ failure among diabetics. Methods and Results— In streptozotocin-induced diabetic mice, we evaluated the potential of human tissue kallikrein (hTK) gene as a sole therapy against peripheral microangiopathy. Local delivery of hTK gene halted the progression of microvascular rarefaction in hindlimb skeletal muscle by inhibiting apoptosis, thus ensuring an improved hemodynamic recovery in case of supervening vascular occlusion. The curative action of hTK did not necessitate insulin supplementation. Application of gene therapy at a stage of established microangiopathy stimulated vascular regeneration. Conclusions— Our studies indicate that hTK may represent a useful tool for the treatment of microvascular complications in diabetics.

Microangiopathy

Thrombotic microangiopathy

10.1161/01.cir.0000027104.33206.c8

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Renovascular Hypertension in Bradykinin B ₂ -Receptor Knockout Mice

Hypertension (1998)

Paolo Madeddu Anna Franca Milia Maria Bonaria Salis Leonardo Gaspa Wolkmar Gross

Abstract —We evaluated whether kinins exert a protective action against the development of two-kidney, one clip (2K1C) hypertension, a model characterized by an activated renin-angiotensin system in the ischemic kidney and increased expression of the bradykinin (BK) B 2 receptor in the contralateral kidney. BK B 2 -receptor knockout (B 2 −/− ), wild-type (B 2 +/+ ), and heterozygous (B 2 +/− ) mice underwent clipping of the left renal artery, with the other kidney remaining untouched. Basal systolic blood pressure (SBP, via tail-cuff plethysmography) was higher in B 2 −/− mice than in B 2 +/− or B 2 +/+ mice (121±2 versus 113±2 and 109±1 mm Hg; P <0.05 for both comparisons). SBP did not change from basal values after sham operation, but it increased in mice that underwent clipping. The increase in SBP was greater in 2K1C B 2 −/− mice than in B 2 +/− or B 2 +/+ mice (28±2 versus 14±2 and 14±2 mm Hg, respectively, at 2 weeks; P <0.05 for both comparisons). Blockade of the BK B 2 receptor by Icatibant enhanced the pressure response to clipping in B 2 +/+ mice (29±2 mm Hg at 2 weeks). Intra-arterial mean blood pressure (MBP) was higher in 2K1C than in respective sham-operated mice, with the MBP difference being higher in B 2 −/− mice (32 and 38 mm Hg, at 2 and 4 weeks, respectively), and higher in B 2 +/+ mice given Icatibant (30 and 32 mm Hg) than in B 2 +/+ mice without Icatibant (17 and 18 mm Hg). At 4 weeks, acute injection of an angiotensin type 1 receptor antagonist normalized the MBP of 2K1C hypertensive mice. A tachycardic response was observed 1 week after clipping in B 2 −/− and B 2 +/− mice, but this effect was delayed in B 2 +/+ mice. However, the HR response to clipping in B 2 +/+ mice was enhanced by Icatibant. Within each strain, heart weight to body weight ratio was greater in 2K1C hypertensive mice than in sham-operated control animals (B 2 −/− : 5.7±0.1 versus 5.2±0.1; B 2 +/+ : 5.1±0.1 versus 4.5±0.1; P <0.01 for both comparisons). The clipped kidney weight to nonclipped kidney weight ratio was consistently reduced in mice with 2K1C hypertension. Our results indicate that kinins acting on the BK B 2 receptor exert a protective action against excessive blood pressure elevation during early phases of 2K1C hypertension.

Renovascular Hypertension

Knockout mouse

Bradykinin receptor

10.1161/01.hyp.32.3.503

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Rescue of Impaired Angiogenesis in Spontaneously Hypertensive Rats by Intramuscular Human Tissue Kallikrein Gene Transfer

Hypertension (2001)

Costanza Emanueli Maria Bonaria Salis Tiziana Stacca Leonardo Gaspa Julie Chao

Angiogenesis represents a compensatory response targeted to preserve the integrity of tissues subjected to ischemia. The aim of the present study was to examine whether reparative angiogenesis is impaired in spontaneously hypertensive rats (SHR), as a function of progression of hypertension. In addition, the potential of gene therapy with human tissue kallikrein (HK) in revascularization was challenged in SHR and normotensive Wistar-Kyoto rats (WKY) that underwent excision of the left femoral artery. Expression of vascular endothelial growth factor and HK was upregulated in ischemic hindlimb of WKY but not of SHR. Capillary density was increased in ischemic adductor muscle of WKY (from 266+/-20 to 633+/-73 capillaries/mm(2) at 28 days, P<0.001), whereas it remained unchanged in SHR (from 276+/-20 to 354+/-48 capillaries/mm(2), P=NS), thus compromising perfusion recovery as indicated by reduced plantar blood flow ratio (0.61+/-0.08 versus 0.92+/-0.07 in WKY at 28 days, P<0.05). In separate experiments, saline or 5x10(9) pfu adenovirus containing the HK gene (Ad.CMV-cHK) or the beta-galactosidase gene (Ad.CMV-LacZ) was injected intramuscularly at 7 days after the induction of ischemia. Ad.CMV-cHK augmented capillary density and accelerated hemodynamic recovery in both strains, but these effects were more pronounced in SHR (P<0.01). Our results indicate that native angiogenic response to ischemia is impaired in SHR, possibly as a result of defective modulation of endothelial cell mitogens. Supplementation with kallikrein, one of the growth factors found to be deficient in SHR, restores physiological angiogenic response utilitarian for tissue healing. Our discoveries may have important implications in vascular medicine for therapeutic benefit.

10.1161/01.hyp.38.1.136

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Citations (79)

Combined Pulmonary Fibrosis and Emphysema (CPFE): a radiological diagnosis

M. V. Graniti Maria Bonaria Salis Giorgio Bagella Paola Crivelli Marco Conti

Poster: ECR 2019 / C-1147 / Combined Pulmonary Fibrosis and Emphysema (CPFE): a radiological diagnosis by: M. V. Graniti 1, M. salis1, G. Bagella1, P. Crivelli2, M. Conti1; 1sassari/IT, 2Sassari, Italy/IT

Pulmonary emphysema

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Prophylactic Gene Therapy With Human Tissue Kallikrein Ameliorates Limb Ischemia Recovery in Type 1 Diabetic Mice

Diabetes (2004)

Costanza Emanueli Gallia Graiani Maria Bonaria Salis Sergio Domenico Gadau Elisa Desortes

Diabetes macro- and microvascular disease causes tissue hypoperfusion. This deficit, together with a failure to mount an adequate angiogenic response, might explain why vascular occlusion evolves more severely among diabetic patients. The present study investigated whether prophylactic gene therapy with human tissue kallikrein (hTK) may protect diabetic limbs from the consequences of supervening ischemia. Vehicle (saline) or an adenovirus carrying the gene for either hTK (Ad.hTK) or luciferase (Ad.Luc) was injected into left adductor muscles of streptozotocin-induced type 1 diabetic mice 2 weeks before operative occlusion of the ipsilateral femoral artery. Saline-injected nondiabetic mice served as controls. Hindlimb blood flow recovery was analyzed sequentially over the 2 weeks after ischemia induction. At necroscopy, microvessel density and endothelial cell proliferation and apoptosis were quantified in skeletal muscles. We found that limb perfusion recovery of saline-injected type 1 diabetic mice is delayed because of insufficient reparative neovascularization and excessive activation of endothelial cell apoptosis. By contrast, prophylactic Ad.hTK renewed the ability to mount an appropriate neovascularization response to ischemia, suppressed apoptosis, and upregulated endothelial nitric oxide synthase expression. Ultimately, correction of diabetic endotheliopathy by Ad.hTK allowed proper perfusion recovery as seen in nondiabetic mice. These discoveries disclose new therapeutic options for the treatment of diabetic complications.

10.2337/diabetes.53.4.1096

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Nerve Growth Factor Promotes Angiogenesis and Arteriogenesis in Ischemic Hindlimbs

Circulation (2002)

Costanza Emanueli Maria Bonaria Salis Alessandra Pinna Gallia Graiani Luigi Manni

Background— The neurotrophin nerve growth factor (NGF) regulates neuron survival and differentiation. Implication in neovascularization is supported by statement of NGF and its high-affinity receptor at vascular level and by NGF property of stimulating vascular endothelial cell proliferation. The present study investigated the involvement of endogenous NGF in spontaneous reparative response to ischemia. Mechanisms and therapeutic potential of NGF-induced neovascularization were examined. Methods and Results— Unilateral limb ischemia was produced in CD1 mice by femoral artery resection. By ELISA and immunohistochemistry, we documented that statement of NGF and its high-affinity receptor is upregulated in ischemic muscles. The functional relevance of this phenomenon was assessed by means of NGF-neutralizing antibody. Chronic NGF blockade abrogated the spontaneous capillarization response to ischemia and augmented myocyte apoptosis. Then we tested whether NGF administration may exert curative effects. Repeated NGF injection into ischemic adductors increased capillary and arteriole density, reduced endothelial cell and myofiber apoptosis, and accelerated perfusion recovery, without altering systemic hemodynamics. In normoperfused muscles, NFG-induced capillarization was blocked by vascular endothelial growth factor–neutralizing antibodies, dominant-negative Akt, or NO synthase inhibition. Conclusions— These results indicate that NGF plays a functional role in reparative neovascularization. Furthermore, supplementation of the growth factor promotes angiogenesis through a vascular endothelial growth factor-Akt-NO–mediated mechanism. In the setting of ischemia, potentiation of NGF pathway stimulates angiogenesis and arteriogenesis, thereby accelerating hemodynamic recovery. NGF might be envisaged as a utilitarian target for the treatment of ischemic vascular disease.

Arteriogenesis

10.1161/01.cir.0000033971.56802.c5

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Dilated and Failing Cardiomyopathy in Bradykinin B ₂ Receptor Knockout Mice

Circulation (1999)

Costanza Emanueli Roberta Maestri Domenico Corradi Roberta Marchione Alessandra Minasi

Background —The activation of B 2 receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure. Methods and Results —To test whether the absence of bradykinin B 2 receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B 2 receptor gene knockout (B 2 −/− ), heterozygous (B 2 +/− ), and wild-type (B 2 +/+ ) mice. The BP of B 2 −/− mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B 2 +/+ , P <0.01). In B 2 +/− mice, BP elevation was delayed. At 40 days, the heart rate was higher ( P <0.01) in B 2 −/− and B 2 +/− than in B 2 +/+ mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B 2 −/− and B 2 +/− mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B 2 +/+ mice. In B 2 −/− mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B 2 +/+ mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B 2 +/+ mice, P <0.01), and reparative fibrosis. Conclusions —The disruption of the bradykinin B 2 receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.

Bradykinin receptor

Knockout mouse

10.1161/01.cir.100.23.2359

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Citations (172)

Nitric Oxide–Releasing Aspirin Derivative, NCX 4016, Promotes Reparative Angiogenesis and Prevents Apoptosis and Oxidative Stress in a Mouse Model of Peripheral Ischemia

Arteriosclerosis Thrombosis and Vascular Biology (2004)

Costanza Emanueli Sophie Van Linthout Maria Bonaria Salis Angela Monopoli Piero Del Soldato

Recently, nitric oxide (NO) donors have been developed that mimic the physiological intracellular release of NO. We evaluated whether one of these new compounds, consisting of aspirin coupled to an NO-releasing moiety (NCX 4016), would protect limbs from supervening arterial occlusion.Mice were assigned to receive regular chow or chow containing NCX 4016 or aspirin (both at 300 mumol/kg body weight, daily) throughout the 3-week experimental period. One week after randomization, they underwent surgical excision of the left femoral artery. Limb blood flow recovery (laser Doppler flowmetry) was accelerated by NCX 4016 as compared with aspirin or vehicle (P<0.05). In controls, histological analysis revealed a 35% increase in the capillary density of ischemic muscles compared with contralateral ones, indicative of spontaneous angiogenesis. Neovascularization was enhanced by NCX 4016 (91%; P<0.05 versus vehicle), but not by aspirin (51%; P=NS versus vehicle). Furthermore, NCX 4016 reduced endothelial cell (EC) apoptosis (4.3+/-1.0 versus 8.7+/-2.0 in aspirin and 12.6+/-3.3 ECs/1000 cap in vehicle; P<0.05 for either comparison) as well as caspase-3 mRNA levels in ischemic muscles ([caspase-3/GAPDH]*100 = 0.09+/-0.04 versus 2.30+/-0.44 in aspirin and 2.30+/-0.32 in vehicle; P<0.01 for either comparison). Nitrite levels and the ratio of reduced to oxidized glutathione were selectively increased in ischemic muscles by NCX 4016. Vascular endothelial growth factor-A expression was reduced by aspirin, with this effect being blunted by NCX 4016.Pretreatment with the new oral NO-releasing aspirin derivative stimulates reparative angiogenesis and prevents apoptosis and oxidative stress, thereby alleviating the consequences of supervening arterial occlusion.

Arteriogenesis

10.1161/01.atv.0000144030.39087.3b

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Citations (27)

Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice

Diabetologia (2004)

Maria Bonaria Salis Gallia Graiani Elisa Desortes Ruth B. Caldwell Paolo Madeddu

Hindlimb

10.1007/s00125-004-1424-5

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Citations (76)