Impaired Wound Repair in Adult Endoglin Heterozygous Mice Associated with Lower NO Bioavailability

Abstract

Endoglin (Eng) is a transmembrane glycoprotein that is mainly expressed in endothelial cells, but it is also present in the epidermis and skin appendages. To address the role of Eng in cutaneous wound healing, we compared the kinetics of reepithelialization in Eng heterozygous null (Eng(+/-)) mice and their normal littermates (Eng(+/+)) following skin wounds. The wound area was significantly larger in Eng(+/-) than in Eng(+/+) mice from 2 to 8 days after injury; overall wound closure was delayed by 1 to 2 days. In Eng(+/-) mice, keratinocytes at the wound edges exhibited impaired proliferation but were more migratory, as shown by their elongated morphology and increased keratin 17 expression. Inhibition of nitric oxide (NO) synthesis delayed healing in Eng(+/+) but not in Eng(+/-) mice. Administration of the NO donor LA-803 accelerated wound closure in Eng(+/-) mice, with no effect on normal littermates. The acute stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced Eng expression in mouse epidermal keratinocytes in vivo and in vitro associated with hyperproliferation. Similarly, the skin of Eng(+/-) mice failed to mount a hyperplastic response to acute stimulation with TPA. These results demonstrate an important involvement of Eng in wound healing that is associated with NO bioavailability.

Endoglin Deficiency Impairs Stroke Recovery

“…Bioavailability of NO is lower in Eng +/− mice than WT mice. 20 NO produced by endothelial cell induces vascular relaxation. 21 Thus, reduced vessel relaxation and increased vascular damage, together with oxidative stress (more superoxide production), in Eng +/− mice enhance brain injury during the acute stage of ischemic stroke.…”

Non-thermal air plasma promotes the healing of acute skin wounds in rats

“…The beneficial effects of NO on wound repair may be attributed to its functional influences on angiogenesis, inflammation, cell proliferation, matrix deposition, and remodelling31. Indeed, high iNOS levels were associated with higher healing rates in chronic leg ulcers32, while impaired wound repair was associated with lower NO bioavailability33.…”

Exploring the in situ expression of vascular endothelial growth factor and endoglin in pemphigus foliaceus variants and pemphigus vulgaris

“…Vascular endothelial growth factor expression is regulated by endoglin, a marker of angiogenesis and a prerequisite for adequate skin restoration . Low endoglin expression activates intracellular pathways that inhibit keratinocyte proliferation and reduce the synthesis of nitric oxide by endothelial cells . Therefore, the decreased anti‐endoglin positivity observed in PF and psoriasis suggests healing processes are impaired in these diseases in comparison with PV.…”

“…14 Low endoglin expression activates intracellular pathways that inhibit keratinocyte proliferation 15 and reduce the synthesis of nitric oxide by endothelial cells. 16 Therefore, the decreased anti-endoglin positivity observed in PF and psoriasis suggests healing processes are impaired in these diseases in comparison with PV. Unbalanced expression of VEGF leads to vasodilation and increased vascular permeability to inflammatory cells, possibly perpetuating the skin damage 17 in psoriasis 9 and PF.…”