Hypertension, a major cardiovascular risk factor and cause of mortality worldwide, is thought to arise from primary renal abnormalities. However, the etiology of most cases of hypertension remains unexplained. Vascular tone, an important determinant of blood pressure, is regulated by nitric oxide, which causes vascular relaxation by increasing intracellular cGMP and activating cGMPdependent protein kinase I (PKGI). Here we show that mice with a selective mutation in the N-terminal protein interaction domain of PKGI␣ display inherited vascular smooth muscle cell abnormalities of contraction, abnormal relaxation of large and resistance blood vessels, and increased systemic blood pressure. Renal function studies and responses to changes in dietary sodium in the PKGI␣ mutant mice are normal. These data reveal that PKGI␣ is required for normal VSMC physiology and support the idea that high blood pressure can arise from a primary abnormality of vascular smooth muscle cell contractile regulation, suggesting a new approach to the diagnosis and therapy of hypertension and cardiovascular diseases.cyclic nucleotides ͉ hypertension ͉ nitric oxide ͉ vascular biology ͉ vascular smooth muscle E levated blood pressure is a major risk factor for cardiovascular diseases and is responsible for widespread morbidity and mortality (1). Blood pressure is regulated by a variety of complex neurohumoral and mechanical signals that together determine systemic vascular tone and resistance (2, 3). The prevailing model for elevated blood pressure states that renal abnormalities of sodium handling cause volume expansion, increased systemic vascular resistance, and hypertension, and a large number of physiologic and genetic studies support this model and the central role of the renal renin-angiotensinaldosterone system in blood pressure regulation (4-8). Changes in vascular morphology and tone can increase vascular resistance and blood pressure (5), but the hypothesis that primary abnormalities of vascular smooth muscle tone can cause hypertension has not been sufficiently tested (6).Vascular smooth muscle contraction is initiated by both calcium-dependent and -independent mechanisms. Increases in intracellular calcium from receptor-or ion channel-activated pathways (2) lead to activation of myosin light chain kinase, which phosphorylates myosin light chains, activating myosin ATPase and increasing vascular smooth muscle cell (VSMC) contraction and vascular tone. The central calcium-independent pathway regulating VSMC tension is mediated by the GTPase RhoA and Rho kinase, which promote VSMC differentiation, stress fiber formation, and contraction, also increasing vascular tone (2, 7). Conversely, VSMC relaxation is mediated by activation of myosin light chain phosphatase (MLCP), which dephosphorylates myosin light chains to cause relaxation. The relative proportion of phosphorylated and dephosphorylated myosin light chains thus determines the state of VSMC tone (reviewed in ref.2). Nitric oxide, the most important endogenous vasodilator, cause...

The midcycle luteinizing hormone (LH) surge triggers several tightly linked ovarian processes, including steroidogenesis, oocyte maturation, and ovulation. We designed studies to determine whether epidermal growth factor receptor (EGFR)-mediated signaling might serve as a common regulator of these activities. Our results showed that EGF promoted steroidogenesis in two different in vitro models of oocyte-granulosa cell complexes. Inhibition of the EGFR kinase prevented EGF-induced steroidogenesis in these in vitro systems and blocked LH-induced steroidogenesis in intact follicles primed with pregnant mare serum gonadotropin. Similarly, inhibition of the EGFR kinase attenuated LH-induced steroidogenesis in MA-10 Leydig cells. Together, these results indicate that EGFR signaling is critical for normal gonadotropin-induced steroidogenesis in both male and female gonads. Interestingly, inhibition of metalloproteinase-mediated cleavage of membranebound EGF moieties abrogated LH-induced steroidogenesis in ovarian follicles but not MA-10 cells, suggesting that LH receptor signaling activates the EGFR by different mechanisms in these two models. Finally, steroids promoted oocyte maturation in several ovarian follicle models, doing so by signaling through classical steroid receptors. We present a model whereby steroid production may serve as one of many integrated signals triggered by EGFR signaling to promote oocyte maturation in gonadotropin-stimulated follicles.ovary ͉ nongenomic ͉ progesterone F emale fertility requires ordered follicular development and growth that ultimately leads to ovulation of mature oocytes in response to a midcycle luteinizing hormone (LH) surge. LH triggers multiple processes within the ovary that are all critical for normal ovulation, including steroidogenesis, cumulus-cell expansion, and oocyte maturation. Understanding the signaling pathways induced by LH in the ovary is therefore essential for appreciating how these activities relate to one another. Several pieces of evidence have implicated epidermal growth factor receptor (EGFR) signaling as a potential central pathway coordinating these important LHmediated events.First, EGF triggers steroidogenesis in gonadal cells, including Leydig cell lines (1, 2) and possibly granulosa cells (3). Whereas EGF promotes steroidogenesis in these models, an essential role for EGF and the EGFR in regulating gonadotropin-induced steroidogenesis has not been established.Second, the EGFR regulates oocyte maturation (4, 5). Maturation refers to the meiotic progression of oocytes from prophase I to metaphase II that is required for normal ovulation and fertilization. LH triggers secretion of EGF molecules, which, in turn, signal in a paracrine fashion through the EGFR to stimulate cumulus-cell expansion and oocyte maturation. Notably, EGF cannot directly trigger maturation of denuded oocytes, suggesting that secondary messengers induced by EGFR signaling in the cumulus cells are required for meiotic progression.Finally, in contrast to EGF, testosterone and es...

Normal fertility in females depends upon precise regulation of oocyte meiosis. Oocytes are arrested in prophase I of meiosis until just before ovulation, when meiosis, or maturation, is triggered to resume. Whereas sex steroids appear to promote maturation in fish and amphibians, the factors regulating mammalian oocyte maturation have remained obscure. We show here that, similar to lower vertebrates, steroids may play a role in promoting the release of meiotic inhibition in mammals. Specifically, testosterone induced maturation of mouse oocytes arrested in meiosis, as well as activation of MAPK and cyclin-dependent kinase 1 signaling. These responses appeared to be transcription independent and might involve signaling through classical androgen receptors expressed in the oocytes. Our results are the first to show that sex steroids can modulate meiosis in mammalian oocytes and suggest a model whereby dominant ovarian follicles in mammals may produce sufficient androgen and/or other steroids to overcome constitutive inhibitory signals and allow oocyte maturation and subsequent ovulation to occur.

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