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Wound healing is a complex physiological process including overlapping phases (hemostatic/inflammatory, proliferating and remodeling phases). Every alteration in this mechanism might lead to pathological conditions of different medical relevance. Treatments for chronic non-healing wounds are expensive because reiterative treatments are needed. Regenerative medicine and in particular mesenchymal stem cells approach is emerging as new potential clinical application in wound healing. In the past decades, advance in the understanding of molecular mechanisms underlying wound healing process has led to extensive topical administration of growth factors as part of wound care. Currently, no definitive treatment is available and the research on optimal wound care depends upon the efficacy and cost-benefit of emerging therapies. Here we provide an overview on the novel approaches through stem cell therapy to improve cutaneous wound healing, with a focus on diabetic wounds and Systemic Sclerosis-associated ulcers, which are particularly challenging. Current and future treatment approaches are discussed with an emphasis on recent advances.

Human studies have shown that the blood pressure lowering effects of angiotensin converting enzyme inhibitors are accompanied by a reduction in plasma norepinephrine levels. Whether this is due to central or peripheral mechanisms is unknown, however.To evaluate the effects of chronic interference with the renin-angiotensin system on sympathetic nerve traffic and baroreflex control of vagal and adrenergic cardiovascular drive.In 18 untreated mild to moderate essential hypertensive patients aged 48.5+/-1.9 years (mean+/-SEM), we measured mean arterial pressure (Finapres), heart rate (electrocardiogram), plasma renin activity (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography) and postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve). In nine patients, measurements were performed before and after 2 months of oral administration of lisinopril (10 mg/day), while in the remaining nine patients they were performed before and after a 2 month observation period, without the drug administration. Measurements were performed at rest and during baroreflex stimulation and deactivation elicited by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively.Lisinopril induced a marked increase in plasma renin activity (from 1.1+/-0.2 to 6.4+/-1.3 ng/ml per h, P0.01) and a reduction in mean arterial pressure (from 109.6+/-3.1 to 98.7+/-2.9 mmHg, P0.01) without affecting the heart rate. Plasma norepinephrine and muscle sympathetic nerve activity values were not significantly different before and after lisinopril treatment (plasma norepinephrine values changed from 290.4+/-39.2 to 308.1+/-67.1 pg/ml; muscle sympathetic nerve activity changed from 56.4+/-5.3 to 50.6+/-6.6 bursts/100 heart beats). Neither the sympathoinhibitory nor the sympathoexcitatory responses to phenylephrine and nitroprusside were affected by lisinopril, nor the concomitant bradycardia and tachycardia. The curves relating mean arterial pressure to heart rate and muscle sympathetic nerve activity values during baroreceptor manipulation were shifted to the left, indicating a resetting of the baroreflex to the lower blood pressure values achieved during treatment. CONCLUSIONS In essential hypertension, sympathetic nerve traffic is not affected by chronic angiotensin converting enzyme inhibitor treatment that effectively interferes with the renin-angiotensin system and lowers the elevated blood pressure. The baroreflex ability to modulate heart rate and central sympathetic outflow is also unaffected. These data argue against the existence of a central sympathoexcitatory effect of angiotensin II in this condition. They also indicate that antihypertensive treatment with an angiotensin converting enzyme inhibitor preserves autonomic reflex control, with favorable consequences for cardiovascular homeostasis.

Experimental animal studies carried out over the past 40 years have unequivocally shown that neurogenic mechanisms are involved in the pathogenesis of hypertension. The results of these studies also suggest that neural factors are important not only in the development but also in the maintenance of the high blood pressure condition. Whether this is the case also for human hypertension has been matter of debate for several decades. However, recent studies in man by employing sophisticated techniques for assessing sympathetic tone, i.e. the norepinephrine radiolabelled technique and microneurographic recording of sympathetic nerve traffic, support the hypothesis that alterations in sympathetic modulation of the cardiovascular system take place in hypertension and may have a pathogenetic relevance in age-related blood pressure increase.

In professional athletes with marked cardiac hypertrophy, reflex influences originating from cardiopulmonary receptors are impaired. To determine whether the reflex is restored after termination of physical training and regression of cardiac hypertrophy 8 former athletes (age 31 +/- 6 years, mean +/- SD) who stopped agonistic activity for 5 +/- 1 years were compared with 15 sedentary subjects (27 +/- 7 years) and 19 active professional athletes (22 +/- 7 years). Cardiopulmonary receptor stimulation and deactivation were obtained by increasing and reducing left ventricular end-diastolic diameter (echocardiography) through leg raising and nonhypotensive lower body negative pressure, respectively. Left ventricular mass index (echocardiography) was markedly and significantly (p less than 0.01) greater in athletes (135 +/- 6 g/m2) than in former athletes (105 +/- 4 g/m2) whose value was similar to that of sedentary subjects (98 +/- 4 g/m2). The reduction in forearm vascular resistance and plasma norepinephrine induced by increasing left ventricular end-diastolic diameter was 24 and 23% less in athletes than in former athletes whose responses were similar to those of sedentary subjects. This was the case also for the responses induced by reducing left ventricular end-diastolic diameter. In contrast, the hemodynamic responses to cold pressor test were similar in the 3 groups. It is concluded that the impairment of the cardiopulmonary reflex observed in athletes is largely reversible when physical training is terminated. This may be due to regression of left ventricular hypertrophy.

Background: Platelets play a central role in atherothrombosis, which is responsible of major cardiovascular complications in human hypertension. Nitric oxide (NO) inhibits platelet aggregation via the second messenger cyclic guanosine monophosphate (cGMP). In essential hypertensives (EHs), we examined the relationship between platelet cGMP and clinical, hemodynamic, humoral variables as well as the responses to aggregating agents. Methods: In untreated EHs (male/female 106/43, age 44.4 1.1 years, smokers yes/no 38/111), blood pressure (BP), heart rate (HR), and stroke volume (SV) (impedance cardiography) were assessed after supine rest and venous blood was sampled for platelet cGMP (radioimmunoassay on acid extracts of washed platelets), plasma cGMP, atrial natriuretic peptide (ANP), renin activity, aldosterone and platelet aggregation to epinephrine (EPI, 5 νmol/l), and adenosine diphosphate (ADP) (4 νmol/l) (optical aggregometry on platelet-rich plasma (PRP)). Results: Platelet cGMP (7.0 0.3 pmol/10 9 cells, mean s.e.m.) was lower in males and smokers than in their counterparts (P 0.01 for both). Among the variables tested, platelet cGMP was related to number of cigarettes (0.21), high-density lipoprotein cholesterol (HDLc) (r = 0.32), aldosterone (r = 0.21), and hemoglobin (0.16); in a multivariate analysis that also included sex, HDLc was the best predictor of platelet cGMP. The aggregating response to EPI (r = 0.28), but not to ADP (r = 0.07, ns), was inversely related to platelet cGMP levels. Conclusions: cGMP in resting platelets of EHs is positively predicted by HDLc and is inversely related to the aggregating response to EPI. It is suggested that a defect of the platelet NO/cGMP system could identify uncomplicated EHs at higher risk of thrombotic events during surges of sympathetic activity. © 2009 American Journal of Hypertension, Ltd.

We appreciate the interest expressed by Drager et al1 for our recent article on the sympathoexcitatory effects of metabolic syndrome (MS) in heart failure patients.2 In brief, in our study we found that sympathetic nerve traffic was markedly increased in heart failure and more so in patients combining this disease with MS. It should be worthy of mention that in our study the additive sympathoexcitation was evident for a similar impairment in left ventricular ejection fraction in the 2 groups, and the major determinants of this exceedingly high adrenergic drive …

Background In the hypothesis that the increased collagen metabolism in the intestinal wall of patients affected by inflammatory bowel disease (IBD) is reflected in the systemic circulation, we aimed the study to evaluate serum level of procollagen III peptide (PIIIP) in peripheral and splanchnic circulation by a commercial radioimmunoassay of patients with different histories of disease. Methods Twenty-seven patients, 17 with Crohn and 10 with ulcerative colitis submitted to surgery were studied. Blood samples were obtained before surgery from a peripheral vein and during surgery from the mesenteric vein draining the affected intestinal segment. Fifteen healthy age and sex matched subjects were studied to determine normal range for peripheral PIIIP. Results In IBD patients peripheral PIIIP level was significantly higher if compared with controls (5.0 ± 1.9 vs 2.7 ± 0.7 μg/l; p = 0.0001); splanchnic PIIIP level was 5.5 ± 2.6 μg/l showing a positive gradient between splanchnic and peripheral concentrations of PIIIP. No significant differences between groups nor correlations with patients' age and duration of disease were found. Conclusions We provide evidence that the increased local collagen metabolism in active IBD is reflected also in the systemic circulation irrespective of the history of the disease, suggesting that PIIIP should be considered more appropiately as a marker of the activity phases of IBD.

OBJECTIVE To clarify the controversial issue of whether autonomic influences modulate vascular nitric oxide-mediated vasodilatation or even directly contribute to production of nitric oxide (NO) via nitroxidergic fibers. METHODS Chronic venous and arterial catheters were implanted in Wistar-Kyoto rats (n = 65) for continuous blood pressure measurement, drug administration and blood sampling. Tonic NO-dependent vasodilatation in the conscious free-moving animal was evaluated as the pressor response to inhibition of NO synthesis by intravenous L-monomethylarginine (a 100 mg/kg intravenous bolus plus 0.5 mg/kg per min infusion for 30 min). Experiments were performed under control conditions, chemical sympathectomy by 6-hydroxy-dopamine, ganglionic blockade by hexamethonium, and surgical denervation of sino-aortic baroreceptors. RESULTS Baseline mean arterial pressure was 100+/-4 mmHg (mean +/- SEM) in control rats and 73+/-3, 62+/-5, and 105+/-10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. The peak increase in mean arterial pressure after administration of L-monomethylarginine was 38+/-3 mmHg in control rats and 51+/-3, 50+/-6, and 63+/-10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. Epinephrine and norepinephrine levels in rats of separate groups of unanesthetized control, sympathectomized and ganglion-blocked animals were measured by high-performance liquid chromatography from an arterial blood sample, the results indicating drastic reductions in levels of both catecholamines in the ganglion-blocked (but not in the sympathectomized) rats compared with those in the control rats. CONCLUSIONS Tonic NO-dependent vasodilatation can normally be maintained in the unanesthetized unrestrained rat irrespective of autonomic or humoral adrenergic influences.

In order to investigate whether angiotensin II (Ang II) may contribute to cardiovascular regulation through facilitation of the adrenergic function, we examined the haemodynamic and humoral effects of the application of lower-body negative pressure (LBNP) in sodium-replete patients with essential hypertension before and after acute and chronic angiotensin converting enzyme (ACE) inhibition. We measured the changes in blood pressure, heart rate, central venous pressure, forearm blood flow, plasma noradrenaline, renin activity and Ang II induced by LBNP of two different magnitudes: a milder one deactivating predominantly the cardiopulmonary receptors (mild LBNP), and a greater one deactivating both the cardiopulmonary and the arterial baroreceptors (strong LBNP). We found that during mild LBNP systemic blood pressure was maintained after acute and chronic ACE inhibition, as in control studies; however, the decrements in forearm blood flow and the increments in forearm vascular resistance caused by LBNP were diminished after ACE inhibition (the latter by 69 and 67%, respectively, in acute and chronic studies), in spite of the fact that the falls in central venous pressure and the increases in noradrenaline (NA) were similar to those observed in control conditions. During strong LBNP, the fall in systemic blood pressure was greater after acute and chronic ACE inhibition than in control conditions and was associated with a reduction in the response of forearm vascular resistance similar to that observed during mild LBNP, while the increments in NA were again superimposable to those seen before ACE inhibition. These alterations in the haemodynamic responses to LBNP induced by ACE inhibition were associated with significant increments in basal plasma renin activity and with marked reductions in Ang II. These findings suggest that even in the sodium-replete state, Ang II exerts a facilitatory action on adrenergic function that is physiologically relevant for the regulation of forearm blood flow and the maintenance of blood pressure during the application of gravitational stresses.