Short- and Long-Term Effects of Sildenafil on Skin Flap Survival in Rats

Hart, Kristopher L.; Baur, Dale A.; Hodam, Jason; Lesoon-Wood, Leslie; Parham, Mary A.; Keith, Karen; Vázquez, Raúl; Ager, Edward; Pizarro, José María Sánchez-Marín

doi:10.1097/01.mlg.0000200792.67802.3b

Cited by 66 publications

(43 citation statements)

References 37 publications

(75 reference statements)

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“…Experimental therapies have attempted to capitalize upon the known role of NO/cGMP signaling in increasing blood vessel diameter [79]. Therapies employing L-arginine, cGMP phosphodiesterase inhibitors, or NO donors can increase tissue survival [80-87]. The finding that TSP1 via CD47 limits NO-stimulated VSMC relaxation in vitro suggested a role in controlling blood flow in vivo.…”

Section: Tsp1-cd47 Regulation Of Blood Flow and Tissue Survivalmentioning

confidence: 99%

Enhancing Cardiovascular Dynamics by Inhibition of Thrombospondin- 1/CD47 Signaling

Isenberg¹,

Frazier²,

Krishna³

et al. 2008

CDT

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Activation of soluble guanylate cyclase by nitric oxide (NO) controls signaling pathways that play critical roles in normal vascular physiology and in the pathogenesis of cardiovascular disease. We have identified the secreted protein thrombospondin-1 as a key regulator of NO signaling. Thrombospondin-1 limits the angiogenic activity of NO in endothelial cells, its vasodilator activity in vascular smooth muscle, and its antithrombotic activity in platelets. Loss of either thrombospondin-1 or its receptor CD47 in transgenic mice results in hyperdynamic responses to NO and reveals the importance of this pathway in normal physiology. Thrombospondin-1 and CD47 null mice show improved abilities to respond to ischemic stress, suggesting that therapeutic targeting of this pathway could benefit patients with a variety of ischemic conditions. We review the preclinical development of therapeutics targeting thrombospondin-1 or CD47 for improving survival of fixed ischemia, ischemia due to aging and peripheral vascular disease, and skin grafting.Keywords ischemic injury; tissue perfusion; angiogenesis; hemostasis; blood flow; nitric oxide; vascular smooth muscle; platelets A. IntroductionCardiovascular disease is the single greatest source of morbidity and mortality in Western societies, affecting more than 80% of people over the age of 65 [1,2]. Manifestations include stroke, macular degeneration, peripheral vascular disease, hypertension, heart and other vital organ failure, heart attack, and poor wound healing. The etiology of cardiovascular disease involves either acute or subacute decreases in blood flow with concurrent under-perfusion of tissue [3]. These flow alterations are associated with changes in the structure of arteries and the contractile function of vascular smooth muscle cells (VSMC) [4,5]. Arteries, the major conduits of blood flow to peripheral tissues, dynamically alter their luminal diameter in response to changing regional tissue metabolic needs. Control of blood flow and arterial diameter is achieved through an integrated system of local and central modifiers that stimulate VSMC relaxation or contraction. Intrinsic regulation of vascular contractility and blood flow is an area of great research interest. Among the currently known locally acting vasodilators, nitric oxide (NO) is perhaps the most critical to cardiovascular health [6]. B. Nitric OxideNO is a gaseous diatomic radical that is produced through the conversion of L-arginine to Lcitrulline by three nitric oxide synthases (nNOS/NOS1, iNOS/NOS2 and eNOS/NOS3) [7,8]. eNOS is the predominant NOS isoform expressed in endothelial cells and platelets. The activity of eNOS is extensively regulated by its subcellular localization, calcium/calmodulin and Hsp90 binding, cofactor levels, and several phosphorylation sites [9]. NO is also generated in low oxygen environments through the nitrite reductase activities of several proteins including hemoglobin, myoglobin, and xanthine oxidase [10][11][12]. Among its several bioactivities, NO is one of ...

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Section: Tsp1-cd47 Regulation Of Blood Flow and Tissue Survivalmentioning

confidence: 99%

Enhancing Cardiovascular Dynamics by Inhibition of Thrombospondin- 1/CD47 Signaling

Isenberg¹,

Frazier²,

Krishna³

et al. 2008

CDT

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show abstract

“…Numerous therapeutic agents have been and continue to be developed for the purpose of selectively increasing tissue blood flow to under-perfused tissue units. In several animal models of tissue ischemia, therapy employing L-arginine, cGMP phosphodiesterase inhibitors, or NO donors has increased tissue survival [111][112][113][114][115][116][117][118]. Since we have identified TSP1 as a major physiological regulator of NOsignaling in vascular cells, we investigated whether TSP1 could likewise regulate tissue blood flow.…”

Section: Tsp1 and Tissue Blood Flow And Survivalmentioning

confidence: 99%

Thrombospondins: from structure to therapeutics

Isenberg

Frazier

Roberts

2008

Cell. Mol. Life Sci.

116

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Thrombospondin-1 is secreted protein that modulates vascular cell behavior via several cell surface receptors. In vitro, nanomolar concentrations of thrombospondin-1 are required to alter endothelial and vascular smooth muscle cell adhesion, proliferation, motility, and survival. Yet, much lower levels of thrombospondin-1 are clearly functional in vivo. This discrepancy was explained with the discovery that the potency of thrombospondin-1 increases more than 100-fold in the presence of physiological levels of NO. Thrombospondin-1 binding to CD47 inhibits NO signaling by preventing cGMP synthesis and activation of its target cGMP-dependent protein kinase. This potent antagonism of NO signaling allows thrombospondin-1 to acutely constrict blood vessels, accelerate platelet aggregation and, if sustained, inhibit angiogenic responses. Acute antagonism of NO signaling by thrombospondin-1 is important for hemostasis but becomes detrimental for tissue survival of ischemic injuries. New therapeutic approaches targeting thrombospondin-1 or CD47 can improve recovery from ischemic injuries and overcome a deficit in NO-responsiveness in aging.

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“…Vasospasm has an important role in the pathogenesis of thrombosis formation and causes ischemic necrosis in flap which can occur during the surgery and after 72 hours (4). Primary ischemia resulted by flap elevation is an important factor for producing flap necrosis, but most flap necrosis develop due to other reasons (2). The activation of the coagulation system by trauma to microvasculature causes flap necrosis (6).…”

Section: Introductionmentioning

confidence: 99%

“…Traumas and oncologic ablations often cause a significant loss of soft tissue accompanied by aesthetic and functional deficits. Regional, pedicle, and free flaps are main surgical approaches for reconstructing these defects (2). Flaps are more appropriate than skin graft because of their color, thickness, consistency, and more similarity to the main tissue (1).…”

Section: Introductionmentioning

confidence: 99%

“…While using random regional or pedicle flaps, length to width ratio is important and an inappropriate design and surgical technique result in ischemic necrosis, wound dehiscence, infection, delayed wound healing, longer hospitalization period, more surgeries, several visits, more morbidity, and higher costs (1). Controlling some factors like smoking and the nutritional status of the patient, avoiding excessive electro cautery, ensuring adequate homeostasis, and preventing tissue injuries such as damage to axial vessels, torsion of the flap pedicle, excessive tension on closure, and strangulation of pedicle during surgery are very important in preventing flap necrosis (2). Width to length ratio is a limiting factor in this type of reconstruction (3).…”

Section: Introductionmentioning

confidence: 99%

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Comparing the Effect of Hirudoid on Random Skin Flap Survival in Rats Based on Different Application Times

Nikoumaram¹,

Fatemi²,

Taghavi³

et al. 2016

Trauma Mon

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Objectives: The objective of the present study was to compare the use of Hirudoid immediately after surgery with its use 6 hours post-operatively when probable thrombosis was formed but tissue damage was still reversible. Methods:After preparing 3 × 11 cm dorsal flap in all rats, one group of 8 rats received Hirudoid topically immediately after surgery during 9 post-operative days. Another group received it 6 h after surgery during 9 post-operative days. The control group received Vaseline immediately after surgery on a daily basis during 9 post-operative days. Results:The mean area of flap survival in the control group was 8.75 ± 3.32 cm 2 (mean ± SD) and it was 12.38±1.93 cm 2 and 14.36 ± 3.51 cm 2 in Hirudoid immediately after surgery and 6 hours after surgery groups, respectively. Conclusions:It was found that Hirudoid can be effective in improving flap viability; although its effect was not statistically significant when used immediately after surgery (P > 0.05), it significantly increased flap survival when used 6 h after surgery (P = 0.003).

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Short- and Long-Term Effects of Sildenafil on Skin Flap Survival in Rats

Cited by 66 publications

References 37 publications

Enhancing Cardiovascular Dynamics by Inhibition of Thrombospondin- 1/CD47 Signaling

Enhancing Cardiovascular Dynamics by Inhibition of Thrombospondin- 1/CD47 Signaling

Thrombospondins: from structure to therapeutics

Comparing the Effect of Hirudoid on Random Skin Flap Survival in Rats Based on Different Application Times

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