*3.5. Altered Gene Expression*

Two studies of first-trimester placental samples at the time of chorionic villous sampling demonstrated differences in gene expression when the woman subsequently developed preeclampsia or fetal growth restriction compared to those who had a normal pregnancy outcome [21,22]. One study which examined gene expression by microarray in first-trimester placentas demonstrated 26 genes were variably expressed in women with high-resistance uterine artery indices. The genes that were significantly differentially expressed included those mainly responsible for cell death/apoptosis, stress response, inflammatory/immune response, and the metabolic and cyclooxygenase pathways [8].

These findings all sugges<sup>t</sup> a close and likely causative association between early-pregnancy uterine artery Doppler indices, trophoblast invasion, and the subsequent development of preeclampsia (Figure 2). High uterine artery resistance indices are predictive of the development of preeclampsia, and also influence trophoblast cell migration, apoptosis, motility, invasion, cell–cell interaction, response to oxidative stress, and gene expression.

**Figure 2.** Relationship between uterine artery perfusion and cellular function. There are strong associations between maternal uterine artery perfusion and placental cellular function and behaviour. High-resistance Doppler indices (poor placental perfusion) is related to abnormalities of cell motility, penetration, and cell–cell interaction, as well as increased rates of oxidative stress, inflammation, cellular injury, and apoptosis. Adapted with permission from Cartwright et al. [23].

#### **4. Uterine Artery Blood Flow and Trophoblast Development—A Causality Paradox**

The relationships demonstrated in the previous section between uterine artery blood flow and trophoblast cell function/behavior have been conventionally interpreted as reflecting the process of trophoblast invasion, causing decreased resistance to flow in the uterine artery. This hypothesis is propagated by the long-held belief that impaired trophoblast development results in poor spiral artery transformation and creates a predisposition to the development of preeclampsia. However, a number of recent findings have led to the re-evaluation of the cause–effect inference between trophoblast development and spiral artery transformation.
