Akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer.

Background: Angiogenesis gene therapy with human tissue kallikrein (hTK) has shown promise for ischemic disease. The present study was undertaken to (1) assess an optimal gene transfer modality, (2) clarify hTK angiogenic pathways, and (3) discount possible side effects.

Methods And Results: The hTK gene was transferred to murine adductors by increasing doses of an adenovirus (Ad.

Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs.

Hematopoietic progenitor cell transplantation can contribute to revascularization of ischemic tissues. Yet, the optimal cell population to be transplanted has yet to be determined. We have compared the therapeutic potential of two subsets of human cord blood CD34+ progenitors, either expressing the VEGF-A receptor 2 (KDR) or not.

Nitric oxide-releasing aspirin derivative, NCX 4016, promotes reparative angiogenesis and prevents apoptosis and oxidative stress in a mouse model of peripheral ischemia.

Background: 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.

Methods And Results: 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.

Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice.

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.

Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice.

Experimental and clinical evidence suggests kinin involvement in adaptive myocardial growth. Kinins are growth-inhibitory to cardiomyocytes. Knockout of kinin B2 receptor (B2R) signaling causes dilated and failing cardiomyopathy in 129/J mice, and a 9-bp deletion polymorphism of human B2R is associated with reduced receptor expression and exaggerated left ventricular growth response to physical stress.

Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs.

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.

Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia.

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-NH2) was assessed in the absence of ischemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin (at 300 and 1.

Prevention of diabetes-induced microangiopathy by human tissue kallikrein gene transfer.

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.

Pharmacological characterisation of [(pX)Phe4]nociceptin(1-13)NH2 analogues. 2. In vivo studies.

As part of a structure-activity study focused on the Phe(4) residue of nociceptin (NC) (1-13)NH(2), we identified two highly potent and selective agonists for the OP(4) receptor, [(pF)Phe(4)]NC(1-13)NH(2) and [(pNO(2))Phe(4)]NC(1-13)NH(2), whose in vitro pharmacological profiles have been described in the companion paper. In the present study, we investigated the actions of [(pF)Phe(4)]NC(1-13)NH(2) and compared it with those of NC(1-13)NH(2) in a battery of vivo assays. In the locomotor activity test in mice, 1 nmol NC(1-13)NH(2) given intracerebroventricularly (i.

Ramipril improves hemodynamic recovery but not microvascular response to ischemia in spontaneously hypertensive rats.

Background: Angiotensin converting enzyme (ACE) inhibition exerts positive effects on the microvasculature of normotensive animals, although this concept is not universally accepted. Recently, ACE inhibitors have been suggested to be useful for rescue in peripheral ischemia.

Methods: We investigated whether chronic treatment with the ACE inhibitor ramipril may have a positive impact on the defective healing response to ischemia that is typical of spontaneously hypertensive rats (SHR).

Angiotensin AT(1) receptor signalling modulates reparative angiogenesis induced by limb ischaemia.

1. The concept that angiotensin II exerts pro-angiogenic activity is not universally accepted. We evaluated whether inhibition of the renin-angiotensin system (RAS) would influence reparative angiogenesis in a murine model of limb ischaemia.