chemotherapy-induced-vascular-toxicity-real-time-vivo-imaging-vessel

Chemotherapy-induced Vascular Toxicity - Real-time <em>In vivo</em> Imaging of Vessel Impairment

Certain classes of chemotherapies may exert acute vascular changes that may progress into long-term conditions that may predispose the patient to an ...

Tel Aviv University

tel aviv university

Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries.

Doxorubicin-induced ovarian toxicity.

Ovarian failure is a-known side-effect observed in women treated for cancer. Doxorubicin (DXR) was found to be detrimental to MII mouse oocytes. We aimed at characterizing the effect of DXR on germinal vesicle (GV) oocytes that comprise the majority of oocytes within ovaries encountering chemotherapy. Mouse follicles and oocytes were exposed to DXR in vitro. DXR localization and its possible cellular targets were examined by fluorescence confocal microscopy. We demonstrated that DXR crosses the blood-follicle barrier and accumulates in oocytes and granulosa cells. The mechanism of DXR-induced apoptosis involves chromosomal disintegration, activation of the mitochondria followed by activation of PERK and caspase-12 and inactivation of PARP. The follicular GV oocytes were more vulnerable to the toxic effect of DXR than ovulated MII oocytes. We suggest that DXR elicits apoptotic signal within GV oocytes that involves activation of the mitochondria, induction of ER-stress and a possible increase in intracellular calcium.

Doxorubicin-induced apoptosis in germinal vesicle (GV) oocytes.

Chemotherapy may induce deleterious effects in normal tissues, leading to organ damage. Direct vascular injury is the least characterized side effect. Our aim was to establish a real-time, in vivo molecular imaging platform for evaluating the potential vascular toxicity of doxorubicin in mice.

In vivo bioimaging as a novel strategy to detect doxorubicin-induced damage to gonadal blood vessels.

Previous study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR) on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized that this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets' activity and interaction with endothelial cells (EC) and to examine potential protectants to reduce DXR acute effect on the blood flow.

Doxorubicin-induced vascular toxicity--targeting potential pathways may reduce procoagulant activity.

Pigment epithelium-derived factor (PEDF) is highly expressed in the female reproductive system and is subjected to regulation by steroid hormones in the ovary. As the uterine endometrium exhibits morphological and functional changes in response to estrogen (E2) and progesterone (P4), we aimed at characterizing the expression of PEDF in this component of the female reproductive tract and further at exploring the hormonal regulation of its expression. We found that PEDF is expressed in human and mouse endometrium. We further showed that this expression is subjected to regulation by steroid hormones, both in vivo and in vitro, as follows: E2 decreased PEDF expression and P4 increased its levels. In human endometrial samples, PEDF levels were dynamically altered along the menstrual cycle; they were low at the proliferative and early secretory phases and significantly higher at the late secretory phase. The expression levels of PEDF were inversely correlated to that of vascular endothelial growth factor (VEGF). We also showed that PEDF receptor was expressed in the endometrium and that its stimulation reduced VEGF expression. Illustrating the pattern of PEDF expression during the menstrual cycle may contribute to our understanding of the endometrial complexity.

Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium.

The physiological function of the female reproductive organs is hormonally controlled. In each cycle, the reproductive organs undergo tissue modifications that are accompanied by formation and destruction of blood vessels. Proper angiogenesis requires an accurate balance between stimulatory and inhibitory signals, provided by pro- and anti-angiogenic factors. As with many other tissues, vascular endothelial growth factor (VEGF) appears to be one of the major pro-angiogenic factors in the female reproductive organs. Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, possessing potent physiologic anti-angiogenic activity that negates VEGF activity. The role of PEDF in decreasing abnormal neovascularization by exerting its anti-angiogenic effect that inhibits pro-angiogenic factors, including VEGF, has been investigated mainly in the eye and in cancer. This review summarizes the function of PEDF in the reproductive system, showing its hormonal regulation and its anti-angiogenic activity. Furthermore, some pathologies of the female reproductive organs, including endometriosis, ovarian hyperstimulation syndrome, polycystic ovary syndrome, and others, are associated with a faulty angiogenic process. This review illuminates the role of PEDF in their pathogenesis and treatment. Collectively, we can conclude that although PEDF seems to play an essential role in the physiology and pathophysiology of the reproductive system, its full role and mechanism of action still need to be elucidated.

Role of pigment epithelium-derived factor in the reproductive system.

To determine whether supplementing granulosa cells cultures with pigment epithelium-derived factor (PEDF) can protect them from oxidative stress.

Article	Year
Doxorubicin-induced ovarian toxicity. Reproductive biology and endocrinology : RB&E\| PubMed ID: 20202194	2010
Doxorubicin-induced apoptosis in germinal vesicle (GV) oocytes. Reproductive toxicology (Elmsford, N.Y.)\| PubMed ID: 20656019	2010
In vivo bioimaging as a novel strategy to detect doxorubicin-induced damage to gonadal blood vessels. PloS one\| PubMed ID: 21931602	2011
Doxorubicin-induced vascular toxicity--targeting potential pathways may reduce procoagulant activity. PloS one\| PubMed ID: 24073244	2013
Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium. Molecular and cellular endocrinology\| PubMed ID: 24769282	2014
Role of pigment epithelium-derived factor in the reproductive system. Reproduction (Cambridge, England)\| PubMed ID: 25049425	2014
Pigment epithelium-derived factor exerts antioxidative effects in granulosa cells. Fertility and sterility\| PubMed ID: 25064413	2014

Hadas Bar-Joseph

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