Intercellular channels or gap junctions (GJ) are formed by connexin (Cx) proteins, transmembrane proteins that play a pivotal role in the direct movement of ions and larger cytoplasmic solutes between vascular endothelial cells (EC), between vascular smooth muscle cells (SMC), and between endothelial and smooth muscle cells (myoendothelial junctions). GJ are clusters of intercellular channels resulting from the connection of two hexameric assembly of Cx (hemichannels). Hemichannels are localized on the membrane of two adjacent cells and arranged with identical or different Cx (21 isoforms in human) with various possible combinations. Such process has functional consequences and provides an efficient cellular strategy to finely regulate cell-to-cell communication in the vascular wall. The expression of different GJ proteins is dynamically regulated throughout different types of vascular bed in healthy vessels and in vascular disease states such as atherosclerosis, systemic and pulmonary hypertension (PH) and diabetes. Our studies focus on the role of intercellular communications (Cx) in the physiology and pathophysiology of the pulmonary arterial vascular bed. In the pulmonary circulation, endothelial control of smooth muscle tone is of critical importance to maintain low pressure and low resistance. In this connection, most of the medical treatments used in PH (e.g., NO, prostacyclin…) mimic and amplify the physiological control of EC on SMC. Myoendothelial junctions may thus potentially participate in this process. We demonstrated that Cx 37, 40 and 43 are expressed and functional in small intrapulmonary arteries (IPA) from rat. Interestingly, resistance vessels are very important for blood flow regulation and the incidence of myoendothelial gap junctions is higher in resistance than in conduit arteries. We also showed that 5-HT, a potent vasoconstrictor whose concentration is increased in PH, produces superoxide anion (O2●) in the smooth muscle and NO in the endothelium. O2● passes through the myoendothelial junctions to decrease endothelial NO production and thus strengthen pulmonary vasoreactivity (Billaud M et al., 2009). Unlike 5-HT, endothelin-1 (ET-1) and phenylephrine (Phe, an α1 adrenoceptor agonist) do not produce O2● in IPA. We investigated the signalling pathways involved in 5-HT-induced O2● production in rat IPA by focusing on the sources of reactive oxygen species (ROS), the role of intra and extracellular calcium and the role of caveolae. This 5-HT-induced production of O2● is mediated by 5-HT2A receptors, is dependent on the complex I of the mitochondrial respiratory chain and NADPH oxidases and extracellular calcium influx plays an important role in this process (Khoyrattee N et al., 2012). We also demonstrated that the main candidates involved in this signaling pathway are localized within/close to caveolae. This is the first time that a negative control of the endothelial NO function by the smooth muscle is demonstrated. PH is a multifactorial disease characterized by a progressive increase in pulmonary vascular resistance caused by vasoconstriction, vascular cell proliferation and obliteration of pulmonary microvasculature. These processes lead to right heart failure and ultimately to death. PH occurs in a variety of clinical situations and is associated with a broad spectrum of histological patterns and molecular abnormalities. Because of this diversity, early diagnosis is difficult and efficient treatments are still lacking. The recent revision of the classification of PH distinguishes five groups. Among these groups, the category 1 PH also known as pulmonary arterial hypertension (PAH) includes idiopathic PAH, familial PAH and acquired PAH, the latter of which being associated with other diseases such as HIV or connective tissue diseases. The non-category 1 PH previously known as secondary PH includes the category 3 which is a widely distributed PH secondary to alveolar hypoxia as a result of lung disease such as chronic obstructive pulmonary disorder (COPD). Although, PH has progressively evolved from a fatal to a chronic disease, none of the currently available therapies is curative. Despite intensive research, PH remains an important medical challenge and a better knowledge of the underlying molecular and cellular mechanisms remains crucial for the development of new or additional innovative therapies. By using different rat models of PH (category 1 and 3) and heterozygous knock-out mice for Cx43, we highlighted Cx43 was overexpressed in PH rats and Cx have some role in the contractile response to stimuli, already known to be involved in PH, namely 5-HT, ET-1, Phe and depolarising solutions (high potassium solutions) (Billaud M et al., 2011; Khoyrattee N et al., 2012). Future directions will be thus to consider Cx as new therapeutic targets and strategies in pulmonary hypertension.