Adult Tissue Angiogenesis: Evidence for Negative Regulation by Estrogen in the Uterus.

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Angiogenesis is the process by which new blood vessels are formed. It does not usually actively occur in adults, with the only non-pathological exception being in the female reproductive organs. Angiogenesis in these tissues is necessary to supply and support the endometrial growth which occurs during different stages in the ovaries and uterus (Yasuda et al, 1998). The ability to understand and manipulate angiogenic factors, therefore controlling angiogenesis would be a major step in controlling different carcinomas and diseases of the female reproductive tract (Fraser, 2003)

In the past research has indicated that stimulation of uterine angiogenesis is induced by estrogen (Hyder and Stancel, 1999). This hypothesis was suggested based on the findings that estrogen(E) rapidly increases vascular permeability, which is then followed by increased angiogenesis. However, Ma et al (2001) have found that while E does causes vascular permeability it actually inhibits angiogenesis (negative regulation), and that it is progesterone(P4) that is responsible for stimulation of angiogenesis, itself having little effect on vascular permeability in the uterus.

One of the ways this is achieved is through up-regulated and rapidly induced expression of the VEGF and FLK1 genes in response to the hormones. Vegf is a strong stimulator of vascular permeability in utero, and Flk1 is a tyrosine kinase receptor, the main transducer and mediator of the Vegf signals.

Commencing with a succinct and comprehensible abstract Ma et al begin by indicating the importance of vascular permeability and angiogenesis in pregnancy, hence establishing the relevance of this study in the field of reproductive research. Through discussion of the roles of the appropriate hormones they clearly justify their research in the fact that definitive knowledge of the functions of these steroids 'remains elusive'. However, having used a mouse model they neglect to relate their findings back to a human model either in the abstract or the rest of the article, barring a brief paragraph in the conclusion which briefly mentions related diseases and conditions affecting pregnancy and the uterus in humans. This does not allow the reader to gain an adequate understanding of the implications this research will have in man.

The aim of this study is clearly presented ('to explore the regulation of angiogenesis in response to steroid hormonal changes in vivo') in both the abstract and the introduction, although a clear hypothesis indicating what the researches are expecting is not presented anywhere within the report. The abstract concludes with a brief summary of the findings in relation to E, P4 and related factors.

An indication of the breadth of this study is provided in the introduction through a listing of the different approaches used eg. Molecular, genetic, physiological and pharmacological. It then continues in a coherent manner providing background information and relevant explanations (including multiple references) ensuring the audience is able to comprehend the following findings and their significance to current knowledge and both past and present research. This is achieved through definition of terms, such as VEGF (vascular endothelial growth factor), presentation of previous knowledge (originally known to be a vascular permeability factor), presentation of current knowledge (now known to also be a potent growth factor) and the supply of references for support.

The results are divided into clear sections which begin with a single sentence which neatly summarises the findings eg. 'E and P4 differentially regulate the spatiotemporal expression of Vegf and Flk1 in the uterus' (these terms and abbreviations having been adequately clarified in the introduction). From here, the writers have expanded and provided detailed results. These have been set out in a sequential manner; each step of the study explained, leading onto the next step. Figures, graphs and photographs are used to encourage easy interpretation of the data. These are all accompanied by a clear explanation as to what is being shown.

Initially Ma et al established that E and P4 regulate the expression of Vegf and Flk1 in the uterus. This was found through comparison of mice divided into four groups, a control group and three experimental groups; the control group receiving oil injections, one experimental group receiving an E injection alone, a second group receiving a P injection alone, and a third group receiving both an E and P4 injection. The methods used to investigate the influence of E and P4 in the mice uteri included northern hybridisation, in situ hybridisation, and lacZ staining.

To ensure the results were valid pertaining to angiogenesis in utero, cell-specific methods were used to eliminate the effects of the heterogenous uterine cell population. However, the sample size of mice used is not stated once in this paper and therefore results cannot be assumed to be significant as a small sample size would not provide enough data to draw reliable conclusions. In addition to this, variation in reactions to the steroid hormones by the individual mice was not considered and it was assumed that all the mice would react in the same way. This may have caused confounding of the results. Also there is no explanation provided as to the reasoning behind the amounts of both oil and hormone administered to the mice. This however, may not have been necessary depending on the assumed readership of the journal. It may have been supposed that ample knowledge of such procedures was already attained, or was not necessary.

Comparison between the control groups and the differing experimental groups is provided by way of percentage differences. This is satisfactory considering the study was not investigating the actual amounts of mRNA present in the uterus, but rather the effect that E and P4 will have on that amount and on the process of angiogenesis. Statistical data and evidence of significance was not provided excepting a short statement declaring significance at the P<0.05 level.

The discussion is clear and statements are supported throughout by referral to results and findings by previous studies. Results obtained from the differing sections of the study are drawn together and the findings are related to each other in a coherent manner, however, as previously mentioned the relation of this data back to a human model is minimal and unsatisfactory. Ma et al also suggest possible reasons for discrepancies between this study and others, such as experimental design and cell types used.

Conclusions are drawn throughout the discussion, which is ended by a review of the results in short and the implications of those results. This conclusion is helpful to the reader as the extent of information covered by this study is so large.

In general this study is clear and easy to understand with the discussion and conclusions understandable and concise. The sheer volume of the results however is overwhelming at first, and processing could be accelerated by the presence of tables or similar to clearly display the findings in a manner that would make for easier comparison and understanding, and more evidence could be provided in relation to the sample size and the significance and reliability of the data.

References

Fraser H. 2003. Regulation and Manipulation of Angiogenesis in the Female Reproductive Tract. Available at:

http://www.hrsu.mrc.ac.uk/research/Hfraser/hfraser.php

Accessed 29.04.04

Hyder SM, Stancel GM. 1999. Regulation of angiogenic growth factors in the female reproductive tract by estrogen and progesterone. Molecular Endocrinology 13 :806 - 811

Yasuda Y, Masuda S, Chikuna M, Inouve K, Nagao M, Sasaki R. 1998. Estrogen dependant production of erythropoiten in uterus and its implications in uterine angiogenesis. Journal of Biological Chemistry 25;273(39): 25381 -7.