Dickkopf2 reprograms damaged erectile tissue toward neurovascular repair through an angiopoietin-1-Tie2 pathway in mice with diabetes mellitus or cavernous nerve injury
Yin, GN1; Ghatak, K1; Choi, MJ1; Minh, NN1; Song, KM1; Ryu, JK1; Suh, JK1
1: Inha University, Korea
Objective: Erectile dysfunction(ED) due to diabetes mellitus(DM) or radical prostatectomy often responds poorly to oral phosphodiesterase-5 inhibitors. Dickkopf2(DKK2), a Wnt antagonist, was recently found to mature vessel formation and promote angiogenesis. We investigated DKK2-mediated signal transduction in the corpus cavernosum and whether and how DKK2 restores penile erection in mouse models of refractory ED.
Material and Methods: DM or cavernous nerve injury(CNI) was induced in wild type or DKK2-Tg mice. We evaluated erectile function by cavernous nerve stimulation, cavernous histology and biochemistry. To further evaluate the role of DKK2-mediated signal transduction, primary (co-)culture of endothelial cell(EC), pericyte and major pelvic ganglion (MPG) were performed from the mouse penis of normal or pathological conditions.
Results: DKK2 was mainly expressed in cavernous pericytes and decreased in both DM and CNI condition. ECs treated with conditioned medium derived from pericytes showed enhanced tube formation, which was impaired by the treatment of DKK2 depleted medium. DKK2-Tg mice or those with intracavernous delivery of DKK2 protein(5mg/20ml) restored erectile function in DM and CNI mice. This recovery by DKK2 in those were accompanied by enhanced proliferation of cavernous ECs and pericytes, evidenced by the increase of CD31(+) with Brdu(+) or p-eNOS(+) and PDGFRc-(+) areafrom the cavernous tissue and by the increase of tube formations from cultured ECs and pericytes. DKK2 treatment also reduced EC permeability by restoration of EC junction proteins in pathologic conditions. Moreover, DKK2 restored nNOS(+) or III tubulin(+) area of corpus cavernosum and promoted neurite sprouting from MPG by enhanced NGF, BDNF, neurotophin3 and TrkA level in pathologic conditions. Transcriptome analysis of ECs revealed that DKK2 treatment upregulates angiopoietin-1 and downregulates angiopoietin-2. Inhibition of this signal with intracavernous delivery of soluble Tie-2 attenuated DKK2-mediated EC proliferation, neurite sprouting and erectile function recovery in those with DM.
Conclusion: DKK2-mediated juxtacrine signaling in pericyte-endothelial cell interactions promotes cavernous angiogenesis and neural regeneration though an angiopoietin-1-Tie2-dependent pathway, rescuing erectile function both in DM and CNI-induced ED. Intracavernous delivery of DKK2 protein reprograms damaged erectile tissue toward neurovascular repair and may open a new avenue to treat ED.
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